Mitochondrially-targeted treatment strategiesLuiz H.M. Bozia,1, Juliane C. Camposa,1, Vanessa O. Zambellib, Nikolas D. Ferreiraa,Julio C.B. Ferreiraa,c,∗
a Institute of Biomedical Sciences, University of Sao Paulo, Brazilb Butantan Institute, Sao Paulo, Brazilc Department of Chemical and Systems Biology, School of Medicine, Stanford University, USA
Disruption of mitochondrial function is a common feature of inherited mitochondrial diseases (mitochon-driopathies) and many other infectious and non-infectious diseases including viral, bacterial and protozoaninfections, inflammatory and chronic pain, neurodegeneration, diabetes, obesity and cardiovascular diseases.Mitochondria therefore become an attractive target for developing new therapies. In this review we describecritical mechanisms involved in the maintenance of mitochondrial functionality and discuss strategies used toidentify and validate mitochondrial targets in different diseases. We also highlight the most recent preclinicaland clinical findings using molecules targeting mitochondrial bioenergetics, morphology, number, content anddetoxification systems in common pathologies.
1. Introduction
Mitochondria play a critical role in ATP synthesis, redox balanceand many other biological processes including ion homeostasis, nucleargene expression, protein turnover and post-translational modificationand apoptosis (Hockenbery et al., 1990; Jo et al., 2001; Mitchell andMoyle, 1969; Nargund et al., 2012; Parrish et al., 2001). More recently,mitochondria have been highlighted as dynamic multi-effector orga-nelles that play unique role in both intra- and inter-cellular commu-nication (Nargund et al., 2012; Tan et al., 2015).
Genetic disruption of mitochondrial metabolism by mutations ineither mitochondrial- or nuclear-encoded proteins is sufficient to triggera large number of inherited diseases termed mitochondrial diseases ormitochondriopathies (e.g. Leigh syndrome and Friedreich's ataxia)(Pfeffer et al., 2012). Moreover, impaired mitochondrial metabolism,morphology, composition and turnover are associated with a widerange of non-mitochondrial diseases including neurodegeneration,cardiovascular diseases, infections, obesity and pain (Sliter et al., 2018;Smyrnias et al., 2019; Sorrentino et al., 2018). Considering the centralrole of mitochondria in the establishment and progression of severaldiseases (Fig. 1), there is an increasing interest from both academia andindustry in developing effective therapeutic approaches focusing onmitochondria metabolism, morphology and content.
Pharmacological strategies targeting mitochondria have been asso-ciated with beneficial effects in a variety of experimental models ofmitochondrial- and non-mitochondrial-related diseases (Foretz et al.,2014; Heitz et al., 2012; Manczak et al., 2010; Smyrnias et al., 2019).Overall, these strategies affect different mechanisms that control mi-tochondrial bioenergetics, oxidative stress, morphology, number, con-tent, surveillance and defense. In this review, we will describe theaforementioned mechanisms in health and disease and discuss pre-clinical and clinical studies targeting mitochondria in different diseasesas well as the current challenges in the field.
2. Mitochondrial (dys)function
Although mitochondria are involved in several intracellular pro-cesses (e.g. intracellular Ca+2 homeostasis, redox balance and apop-tosis), the core function of these organelles is the generation of ATPthrough oxidative phosphorylation (Campos et al., 2016; Danial et al.,2003; Luongo et al., 2017). Mitochondria use a variety of carbonsources (e.g. pyruvate, fatty acids and amino acids) to feed the tri-carboxylic acid (TCA) cycle in the mitochondrial matrix to produce thereducing equivalents NADH and FADH2. The electrons carried byNADH and FADH2 are transferred along the multi-subunits complexes I-IV of the electron transport chain (ETC) to the terminal electron
https://doi.org/10.1016/j.mam.2019.100836Received 22 October 2019; Received in revised form 11 December 2019; Accepted 13 December 2019
∗ Corresponding author. Instituto de Ciências Biomédicas da Universidade de São Paulo-Departamento de Anatomia, Av. Professor Lineu Prestes, 2415, São Paulo,SP, CEP 05508-000, Brazil.
acceptor oxygen. While the electrons pass through the ETC, hydrogenions are pumped from the matrix to the intermembrane space, gen-erating a proton motive force that is used by the ATP synthase (complexV) to synthetize ATP (Murphy and Hartley, 2018; Weinberg andChandel, 2015). This dynamic process relies on several inter- and intra-compartmental regulatory mechanisms (discussed below) capable ofensuring that sufficient ATP is available to match the oscillatory energydemand under a variety of conditions such as exercise and caloric re-striction (Andreux et al., 2013; McCormack et al., 1990; Puigserveret al., 1998; Wu et al., 1999).
In this context, mutations in either nuclear or mitochondrial genesthat encode subunits of the ETC complexes often have a negative effectin a variety of organs and systems including heart (cardiomyopathy),brain (encephalopathy, ataxia and dementia), eye (atrophy and re-tinopathy), kidney (renal failure), bone marrow (anemia), liver (hepa-tophaty) and peripheral nervous system (myopathy, neuropathy)(Abdulhag et al., 2015; Ahlqvist et al., 2012; Emma et al., 2016; Heitzet al., 2012; Wan et al., 2016). Moreover, impaired mitochondrialbioenergetics is a common feature of chronic degenerative diseasesincluding heart failure, skeletal myopathies, neurodegeneration anddiabetes (Campos et al., 2017; Ferreira et al., 2019; Kelley et al., 2002;Petersen et al., 2004; Sorrentino et al., 2017).
Mitochondria also play critical role in many other intracellularprocesses including redox balance, aldehyde metabolism, ion home-ostasis and synthesis of several macromolecules such as amino acids,nucleotides and fatty acids. Therefore, disruption of mitochondrialfunction under pathological conditions is not limited to reduction ofintracellular ATP levels. Accumulation of reactive oxygen species (ROS)and reactive nitrogen species (RNS), aldehydic burden, calcium over-load, impaired potassium handling and defective synthesis of macro-molecules are all mitochondrially-related processes tightly associatedwith the establishment and progression of several diseases includingAlzheimer, Parkinson, heart failure, diabetes, hypertension and obesity(Burbulla et al., 2017; Campos et al., 2017; Gilbert, 1975; Kowaltowskiet al., 1996; Kwong and Molkentin, 2015; Nishikawa and Araki, 2007;
Starkov, 2008). Therefore, the development of novel interventionscapable of restoring mitochondrial function might become a feasiblestrategy to counteract the progression of degenerative diseases(Disatnik et al., 2015).
2.1. Regulation of mitochondrial metabolism
Mitochondrial metabolism is coordinated by a plethora of intra- andextra-mitochondrial signals that ultimately affect every single processwithin the cell. Slight fluctuations in the levels of metabolites, ions andreactive species drive the rapid adjustment of mitochondrial metabo-lism under baseline conditions and upon stress. All these responses aredirectly regulated by (but not limited to) mitochondrial membranepotential. Indeed, mild reduction in proton motive force is sufficient toinduce compensatory mechanisms that affect mitochondrial oxygenconsumption, ATP synthesis, redox state, solute transport, protein im-port, morphology and turnover (Campos et al., 2016; Geissler et al.,2000; Miceli et al., 2011; Zorova et al., 2018). As expected, events thatultimately exceed this compensatory threshold result in excessive mi-tochondrial depolarization, mitochondrial dysfunctional and cell death;therefore, contributing to several diseases (Kenwood et al., 2014; Zhouand Tian, 2018).
Overall, the effectiveness of these transiently coordinated (com-pensatory) responses relies mainly on the number, state and location ofmitochondrial primary effector proteins, which usually work as dy-namic entities of multiprotein complexes that catalyze biochemicalreactions within the mitochondria (Budas et al., 2012; Qvit et al.,2016). Therefore, every step associated with the synthesis, turnover andposttranslational modification of these mitochondrial effector proteinshas an impact on mitochondrial metabolism.
Mitochondria are comprised of approximately 1200 resident (ef-fector and regulatory) proteins mainly encoded by nuclear DNA (only13 mitochondrial proteins are encoded by mitochondrial DNA) (Calvoet al., 2016; Pagliarini et al., 2008). Mitochondria also contain non-resident proteins that are either imported through specialized
Abbreviations
4-HNE 4-hydroxy-nonenalALC acetyl-L-carnitineAlda-1 aldehyde dehydrogenase activator 1ALDH aldehyde dehydrogenaseAMPK AMP-activated protein kinaseANT adenine nucleotide translocaseATF5 activating transcription factor 5ATFS-1 activating transcription factor associated with stress 1ATP adenosine triphosphateβIIPKC βII protein kinase CCoQ10 Coenzyme Q10CREB1 cAMP-responsive element-binding proteinDrp1 dynamin-related protein 1ETC electron transport chainER endoplasmic reticulumFis1 mitochondrial fission 1 proteinFDA Food and Drug AdministrationFOXO forkhead box protein OFUNDC1 FUN14 Domain Containing 1GTPases guanosine triphosphatasesH2O2 hydrogen peroxideHFpEF heart failure with preserved ejection fractionHFrEF heart failure with reduced ejection fractionLHON Leber's Hereditary Optic NeuropathyMAM mitochondria associated membranesMDA malondialdehyde
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mitochondrial TIM/TOM complex or located at mitochondrial outermembrane. These proteins enable the maintenance and fine-tuning ofmitochondrial metabolism through physical and biochemical mi-tochondrial communication with the rest of the cell (for review see(Garesse and Vallejo, 2001; Jovaisaite and Auwerx, 2015)).
The regulation of mitochondrial metabolism involves both ante-rograde and retrograde mitochondrial communication (da Cunha et al.,2015; Weinberg and Chandel, 2015). Anterograde communication re-fers to any signal coming from the cytosol that affects mitochondrialmetabolism (Gehlert et al., 2015). For example, increased cytosoliccalcium oscillations during cardiac or skeletal muscle contraction ulti-mately lead to a rapid sequestration of calcium into the mitochondrialmatrix; therefore, stimulating TCA and oxidative metabolism(McCormack et al., 1990; Weinberg and Chandel, 2015).
Disruption of anterograde mitochondrial communication is suffi-cient to impair mitochondrial bioenergetics under either baseline orstressed conditions (Gehlert et al., 2015; Santulli et al., 2015). For ex-ample, during heart failure there is an excessive accumulation of cal-cium in the cytosol of cardiomyocytes, which negatively effects ex-citation-contraction coupling (Ferreira et al., 2011b; Palaniyandi et al.,2011). Under this scenario, mitochondria start to uptake large amountof calcium to neutralize its cytosolic deleterious effects. However, mi-tochondrial calcium overload results in reduction of ATP productionand increased ROS release (Santulli et al., 2015). Moreover, this cal-cium overload leads to mitochondrial permeability transition pore(mPTP) opening-induced apoptosis (Kowaltowski et al., 1996; Kwongand Molkentin, 2015).
The signal from mitochondria to the rest of the cell is termed
retrograde communication and involves multiple players includingATP, ADP, NAD+, ROS, RNS, TCA metabolites and mitochondrial-de-rived peptides (Andreux et al., 2013; da Cunha et al., 2015; Weinbergand Chandel, 2015). For example, the transport of citrate to the cytosolallows mitochondria to regulate the activity of cytosolic proteins, whileits cleavage by cytosolic enzymes generates acetyl-CoA, which can af-fect protein acetylation – a reversible post-translational modificationthat changes cellular metabolism (Kaelin and McKnight, 2013; Murphyand Hartley, 2018; Wellen et al., 2009). Mitochondrial unfolded proteinresponse also triggers a cytosolic signaling pathway that ultimatelyleads to increased expression of nuclear-encoded mitochondrial pro-teins; therefore adjusting mitochondrial metabolism (Bozi et al., 2019;Haynes et al., 2007; Houtkooper et al., 2013). All these new insightsinto the mechanisms involved in mitochondrial metabolic commu-nication might be considered as potential pathways for interventions totreat a range of degenerative diseases, including mitochondriopathies.
2.2. Mitochondrial biogenesis
Mitochondrial biogenesis is the process by which cells increasemitochondrial mass in order to boost ATP production and attend anycellular, tissue or organ metabolic demand. This process requires acoordinated cross-regulation between mitochondria and nucleus;therefore resulting in increased protein expression of both mitochon-drial- and nuclear-encoded mitochondrial proteins (Garesse andVallejo, 2001; Jovaisaite and Auwerx, 2015). The transcription of bothmitochondrial and nuclear genomes is coordinated by the peroxisomeproliferator-activated receptor gamma coactivator 1α (PGC1α), which
Fig. 1. Mitochondrial dysfunction, usuallycharacterized by a combination of the pro-cesses described above, plays a central rolein several diseases. Energy imbalance: im-paired mitochondrial bioenergetics de-creases cellular viability by limiting the ATPsupply. Altered calcium (Ca2+) flux: ex-cessive mitochondrial calcium uptake trig-gers cell death by the opening of mi-tochondrial permeability transition pore(mPTP). Oxidative stress/aldehydic load: ac-cumulation of reactive oxygen species(ROS) and byproducts of lipid peroxidationsuch as 4-hydroxynonenal (4-HNE) propa-gate mitochondria-mediated cell death.Disrupted proteostasis: accumulation of mi-tochondrial unfolded proteins and/or dis-ruption of stoichiometry between nuclearand mitochondrially encoded ETC subunitsimpairs mitochondrial function. Reducedbiogenesis: decreased transcription of mi-tochondrial genes reduces mitochondrialmass affecting energy metabolism. Fusion-fission imbalance: disrupted mitochondrialmorphology due to impaired fusion or ex-cessive fragmentation has a negative impacton the organelle function. Impaired mito-phagy: reduced degradation of mitochondriathrough mitophagy maximizes mitochon-drial dysfunction. DNA mutations: mutationsin either nuclear or mitochondrial genesencoding mitochondrial proteins triggersorganelle dysfunction.
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is activated under conditions of increased energy demand, such as ex-ercise, cold or fasting (Kelly and Scarpulla, 2004; Puigserver et al.,1998).
PGC1α induces mitochondrial biogenesis by interacting with severaltranscription factors (Kelly and Scarpulla, 2004; Wu et al., 1999).PGC1α binds to and coactivates the nuclear respiratory factor (NRF) 1and 2; therefore inducing the expression of mitochondrial proteinsencoded by nuclear DNA (Wu et al., 1999). The interaction of PGC1αand NRF-1 also promotes the replication of mtDNA through inductionof mitochondrial transcription factor A (Tfam) (Kelly and Scarpulla,2004). Moreover, PGC1α stimulates estrogen-related nuclear receptors,leading to the expression of genes involved in glucose, fatty acid uptakeand ATP production (Dufour et al., 2007; Huss et al., 2004). There areothers transcription factors that affect mitochondrial biogenesis, in-cluding forkhead box protein O (FOXO), cAMP-responsive element-binding protein (CREB1) and peroxisome proliferator activated re-ceptor (PPAR), and a detailed consideration of those is covered else-where (Komen and Thorburn, 2014; Sorrentino et al., 2018).
The activation of mitochondrial biogenesis-related transcriptionfactors can also be affected by post-translation modifications. For ex-ample, when energy supply does not match cellular demand, there is anactivation of the signaling pathway driven by the energy sensor AMP-activated protein kinase (AMPK), which results in the phosphorylationof PGC1α and mitochondrial biogenesis (Andreux et al., 2013; Cantoet al., 2010). Similarly, increased levels of NAD + activate sirtuin 1,which favors mitochondrial biogenesis and oxidative metabolism bydeacetylation of PGC1α (Canto et al., 2009, 2010; Rodgers et al., 2005).
Impaired mitochondrial biogenesis is implicated in several pathol-ogies, including cardiovascular and metabolic diseases (Heinonen et al.,2015; Pisano et al., 2016). Genetic disruption of mitochondrial bio-genesis causes loss of neurons, cardiac dysfunction, insulin resistanceand abnormal thermogenic response in rodents (Arany et al., 2005;Jiang et al., 2016; Kleiner et al., 2012). As expected, induction of mi-tochondrial biogenesis through PGC1α overexpression delays loco-motor dysfunction with aging (Gill et al., 2018). Therefore, enhancingmitochondrial biogenesis may represent another important therapeuticstrategy to tackle mitochondrial dysfunction.
3. Mitochondrial detoxifying approaches
Impairment of mitochondrial bioenergetics usually results in ex-cessive production and accumulation of reactive molecules that canbecome harmful to organisms according to their intracellular con-centration and location (for review see (Campos et al., 2016; Figueiraet al., 2013)). Under mitochondrial stress, electrons can prematurelyreact with oxygen in the ETC and generate excessive ROS; therefore,disrupting mitochondrial and cellular homeostasis by targeting pro-teins, lipids and DNA (Droge, 2002; Wang et al., 2008). For example,there is an extensive production of ROS by reverse electron transport atmitochondrial complex I during ischemia-reperfusion injury(Chouchani et al., 2014). Excessive ROS can also attack mitochondrialmembranes – process known as lipid peroxidation, and generates highlyreactive, lipophilic and damaging molecules termed aldehydes(Esterbauer et al., 1991). Accumulation of these reactive moleculesmaximizes mitochondrial dysfunction and propagates mitochondria-mediated cell death (Kiyuna et al., 2018). Of interest, compartmenta-lized ROS production under physiological conditions positively reg-ulates a plethora of cellular processes including regulation of calciumhandling and protein turnover and activity.
A variety of detoxifying systems has been evolved during evolutionto counteract the toxic and degenerative effect of excessive ROS andaldehydes accumulation. These systems are capable of metabolizingROS and aldehydes into non-toxic forms; therefore, preventing oxygen-and aldehyde-induced cellular damage. In fact, activation of mi-tochondrial detoxifying systems plays a positive effect in a broadspectrum of pathological conditions (Figueira et al., 2013; Murphy
et al., 2016). However, due to the subtle differences between ad-vantageous and detrimental effects of these reactive molecules inbiology, identifying effective interventions able to neutralize themwithin a range that is compatible with redox signaling remain a majorchallenge in a clinical perspective.
3.1. Mitochondrial oxidative stress and redox signaling
Oxidative stress is a metabolic state characterized by accumulationof free radicals (due to an imbalance between free radicals generationand removal) that negatively affects cell biology. Mitochondrial oxi-dative stress is involved in both mitochondriopathies and chronic de-generative diseases. For example, point mutations in the ETC complexeslead to a massive ROS accumulation in Leber hereditary optic neuro-pathy; therefore contributing to disease progression (Lin et al., 2012;Quintana et al., 2010). ROS-induced toxicity is also involved in thepathogenesis of Friedreich's Ataxia – the most prevalent inheritedataxia characterized by mitochondrial iron accumulation-inducedneurological and cardiac degeneration (Ast et al., 2019; Gomes andSantos, 2013).
The free radicals superoxide (O2•−) and hydroxyl radical (•OH),
along with non-radicals such as hydrogen peroxide (H2O2) are oftenreferred as ROS. Mainly originated due to electron leakage at the ETCcomplexes I and III, O2
•− is quickly dismutated to H2O2 by the mi-tochondrial superoxide dismutase (SOD). Although more stable andacting as a second messenger within the cell, H2O2 can be reduced intothe highly reactive molecule •OH in a metal-dependent reaction.Likewise, O2
•− can react with nitric oxide (NO•) – a RNS, generatingperoxynitrite (ONOO•) (Murphy, 2009). Considering that these oxidantsplay a role in cellular physiology (Droge, 2002), a variety of detoxifyingmechanisms (e.g. SOD, catalase, glutathione) act together to maintainROS and RNS at nanomolar levels; therefore preserving cellular viabi-lity. Mitochondria are considered the major source of O2
•−. The absenceor reduced activity of the mitochondrial form of SOD, which results inaccumulation of O2
•− and mitotoxicity, is associated with severalpathologies including perinatal death (Li et al., 1995), dilated cardio-myopathy (Morten et al., 2006), optic neuropathy (Qi et al., 2003),encephalopathy and movement disorders in rodents (Melov et al.,1998).
During ATP synthesis, mitochondria reduce 99% of the molecularoxygen available within the cell, thereby producing H2O. Under phy-siological conditions, a small portion of the total amount of oxygenavailable within the cell (~0.12–2%) generates ROS (Murphy, 2009).This amount can progressively increase under pathological conditionsand contribute to tissue degeneration (i.e. cardiovascular diseases)(Ferreira et al., 2019). However, ROS can also accumulate (transiently)under physiological conditions (termed redox signaling) and con-tributes to long-term adaptations (Campos et al., 2013).
Interventions that activate mitochondrial redox signaling (e.g. ca-loric restriction and physical exercise) extend lifespan and/or promotestress resistance in a variety of organisms (Campos et al., 2018; Cunhaet al., 2012; Pinto et al., 2018; Schulz et al., 2007). It has been proposedthat this mild and transient increase in ROS levels triggers a protectiveresponse termed mitohormesis (Ristow and Schmeisser, 2011; Ristowand Zarse, 2010), which can be mitigated by antioxidants (Ristow et al.,2009; Schulz et al., 2007). However, the mechanisms involved in mi-tohormesis are not fully elucidated. Therefore, determining both levelsand dynamics of ROS during physiological and pathological conditionsby using reliable and sensitive measurements as well as deciphering themolecular mechanisms involved in mitohormesis are critical to pursuetherapies targeting redox homeostasis (Kowaltowski, 2011).
3.2. Mitochondrial aldehydic load
Oxidation of phospholipids located in the mitochondrial innermembrane, termed lipid peroxidation, is itself a source of new
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mitochondrial reactive molecules, such as aldehydes and ketones(Esterbauer et al., 1991). Similarly to ROS and RNS, the concentrationof these byproducts can either trigger beneficial or detrimental sig-naling pathways (Dianzani, 2003; Xiao et al., 2017). Among the lipidperoxidation-derived aldehydes, malondialdehyde (MDA) – the mostabundant, and 4-hydroxy-nonenal (4-HNE) – the most reactive, play acritical role in mitochondrial function, according to their concentrationand location (Barrera et al., 2018; Chen et al., 2014; Ueta et al., 2017;Voulgaridou et al., 2011). These molecules not only have the ability tocovalently bind to proteins and DNA, but also orchestrate metabolicreprogramming (Zhong and Yin, 2015), immune responses (Papac-Milicevic et al., 2016) and apoptosis (Yang et al., 2018). Moreover, 4-HNE is a relatively stable and lipophilic molecule which permeatescellular membranes and propagates the damage to other compartments,cells and systems through the body (Jacobs and Marnett, 2010). In thiscontext, aldehyde-induced adducts might be considered useful bio-markers in detecting and monitoring the establishment and progressionof diseases, respectively (Heymann et al., 2018).
Although 4-HNE is considered an important mediator of oxidativedamage, it may also have a beneficial role at low concentration. 4-HNE(1uM) induces a mild mitochondrial uncoupling by, at least in part,increasing proton leak through the interaction with both adenine nu-cleotide translocase (ANT) – a carrier that exchanges ATP with ADPacross the inner membrane, and uncoupling proteins (e.g. UCP1, UCP2and UCP3) – transporters capable of dissipating the proton gradientgenerated during the ETC (Echtay et al., 2003). As expected, this milduncoupling reduces reactive species levels and improves cellular via-bility under oxidative stress conditions (Breitzig et al., 2016; Papa andSkulachev, 1997; Weisova et al., 2012).
Mammals display a full set of enzymes capable to converting lipidperoxidation byproducts into less reactive chemicals species. Alcoholdehydrogenases and aldo-keto reductases can reduce MDA and 4-HNEto alcohols (Singh et al., 2015), while aldehyde dehydrogenases (ALDH)can oxidize these aldehydes into acids (Marchitti et al., 2008). Inbornerrors related to these detoxifying mechanisms are the molecular basisfor pathologies such as Sjögren-Larsson syndrome and type II hyper-prolinemia (Marchitti et al., 2008). ALDH is a superfamily of 19 geneswith a wide range of tissue distribution and substrates. Located in themitochondrial matrix, ALDH2 plays a critical role in oxidizing bothacetaldehyde (ethanol metabolism byproduct (Josan et al., 2013;Klyosov et al., 1996) and 4-HNE (lipid peroxidation metabolism by-product).
Reduced ALDH2 activity – driven by a single amino acid substitu-tion (ALDH2*2), affects ~560 million East Asians (the most commonenzymopathy in humans) and leads to a well-characterized alcoholflushing phenotype along with dizziness, vomiting and palpitation afteralcohol intake (Brooks et al., 2009). Pharmacological inhibition ofALDH2 is used to treat alcohol abuse, as acetaldehyde accumulation-induced uncomfortable symptoms discourage the alcohol consumption(Koppaka et al., 2012). ALDH2 deficiency is also linked to cardiovas-cular diseases (Munzel and Daiber, 2018), neurodegeneration (Chenet al., 2016) and esophageal, colorectal and breast cancers (Changet al., 2017). Moreover, either pharmacological or genetic inhibition ofALDH2 mitigates ischaemic- or ethanol-cardiac preconditioning in ro-dents (Contractor et al., 2013; Ueta et al., 2018).
Accumulation of 4-HNE is sufficient to disrupt mitochondrial alde-hyde metabolism thorough its physical interaction with critical cy-steines located at ALDH2 catalytic site (Yoval-Sanchez and Rodriguez-Zavala, 2012). This response leads to ALDH2 inactivation and con-sequent propagation of mitochondrial metabolic stress (Gomes et al.,2014). Pharmacological activation of ALDH2 using Alda-1 – a selectivesmall molecule, is sufficient to remove excessive 4-HNE and improvethe outcome of different diseases including ischemia-reperfusion injury,heart failure and inflammatory pain in rodents (Chen et al., 2008;Gomes et al., 2014; Ueta et al., 2018; Zambelli et al., 2014). Moreover,Alda-1 improves the safety of other drugs metabolized by ALDH2 such
as nitroglycerin (Sun et al., 2011). In this case, ALDH2 works as a re-ductase enzyme (Ferreira and Mochly-Rosen, 2012). ALDH2 activatorsmight also play an important role in the metabolism of antiviral drugs(i.e. valaciclovir, acyclovir and CMMG) since individuals carrying theALDH2*2 mutation have reduced elimination rate of antiviral drugs(Gross et al., 2015; Hara et al., 2008).
4. Improving mitochondrial proteostasis
Mitochondria evolved from a proteobacteria that was engulfed by aprecursor eukaryotic cell over a billion years ago (Gray et al., 1999).This evolutionary process poses several challenges for the maintenanceof mitochondrial proteostasis. Only 13 proteins (all subunits of the ETC)are encoded by mtDNA. Approximately 1200 mitochondrial proteinsare derived from nuclear-encoded genes, translated in the cytosol andimported into the mitochondria. The number of proteins encoded bymitochondrial and nuclear genomes must be stoichiometrically ba-lanced in the ETC complexes (Campos et al., 2016; Jovaisaite andAuwerx, 2015; Pagliarini et al., 2008).
Mitochondria have a specialized quality control machinery involvedin protein import, folding, assembling and degradation (Campos et al.,2016; Jovaisaite and Auwerx, 2015; Moehle et al., 2019). Mitochon-drial chaperones are essential for protein folding, localization and as-sembling of ETC complexes, as well as stabilization and re-folding ofmisfolded proteins (Campos et al., 2016; Pellegrino et al., 2013). Forexample, downregulation of the mitochondrial chaperone Hsp60 trig-gers changes in mitochondrial morphology and impairs organellefunction, leading to insulin resistance and locomotor dysfunction inmice (Kleinridders et al., 2013; Magnoni et al., 2013). Similarly,knockout mice for the mitochondrial chaperone mtHsp90 display im-paired mitochondrial respiration and exacerbated oxidative stress(Lisanti et al., 2014).
Complementary to chaperones, proteases are involved in the re-moval of mitochondrial targeting signal as well as recognition anddegradation of proteins that fail to fold or assemble properly (Koppenand Langer, 2007; Quiros et al., 2015). Defective mitochondrial pro-teolytic activity usually results in pathological phenotypes. For ex-ample, cardiac-specific ablation of the mitochondrial protease YME1Limpairs mitochondrial metabolism and induces heart failure (Wai et al.,2015). Mice lacking YME1L in the nervous system manifest oculardysfunction and develop deficiencies in locomotor activity due to spe-cific degeneration of spinal cord axons (Sprenger et al., 2019). Loss ofthe mitochondrial protease SPG7 causes mitochondrial dysfunction,shorten lifespan and triggers neuronal and muscular degeneration inDrosophila (Pareek et al., 2018). Overall, these findings highlight thecritical role of mitochondrial chaperones and proteases in health anddisease. In that sense, small molecules or other interventions capable ofimproving mitochondrial surveillance and defense systems might be-come attractive approaches to rescue mitochondrial metabolism.
Transient perturbations that result in accumulation of unfoldedproteins inside mitochondria is sensed and communicated to the nu-cleus through a signaling pathway termed mitochondrial unfoldedprotein response (UPRmt). This retrograde signaling pathway allowsmitochondria to adjust to conditions that impair proteostasis by in-creasing protein levels of nuclear-encoded mitochondrial chaperonesand proteases (Haynes et al., 2007; Houtkooper et al., 2013; Zhao et al.,2002).
UPRmt was first described in the nematode Caenorhabditis elegans(Haynes et al., 2007). It is suggested that mitochondrial stress inducescleavage of unfolded proteins inside the mitochondria and consequentrelease of peptides through HAF-1 transporter. These still unknownpeptides activate the transcription factor ATFS-1 (activating transcrip-tion factor associated with stress 1) along with UBL-5 and DVE-1,thereby inducing transcription of genes involved in mitochondrialquality control, glycolysis and innate immune response (Benedettiet al., 2006; Haynes et al., 2007, 2010; Nargund et al., 2012). The
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UPRmt machinery is also conserved in mammals and works throughactivation of the transcription factor ATF5 (Aldridge et al., 2007;Jovaisaite and Auwerx, 2015; Martinus et al., 1996).
Genetic or pharmacologic disruption of the stoichiometry betweennuclear- and mitochondrially-encoded ETC subunits impairs mi-tochondrial function and activates UPRmt, which is sufficient to in-crease lifespan in worms (Borch Jensen et al., 2017; Durieux et al.,2011; Houtkooper et al., 2013). Similarly, disruption of mitochondrialproteostasis by knocking down the protease ClpP also promotes acompensatory activation of the UPRmt, which is followed by improvedinsulin resistance and protection against high fat diet-induced obesityin mice (Bhaskaran et al., 2018). Human cells with impaired UPRmtdisplay mitochondrial dysfunction and impaired recovery from pro-teotoxic stress (Fiorese et al., 2016). Overall, these findings point outUPRmt as critical player in the maintenance of mitochondrial pro-teostasis and highlight the potential therapeutic value of UPRmt acti-vators in counteracting the deterioration of mitochondrial functioncaused by accumulation of unfolded proteins.
5. Maintenance of mitochondrial healthy pool
Mitochondria exist as a dynamic and heterogeneous network thatundergoes continuous fusion, fission and turnover (mitophagy) (Hillet al., 2012). These processes are critical to adjust mitochondrialnumber and size according to cell, tissue and organ metabolic demandin health (i.e. exercise) and disease (i.e. heart failure). As expected,sustained disruption of these processes might result in accumulation ofeither fragmented or larger mitochondria with a negative impact onmitochondrial function and organism viability.
5.1. Mitochondrial dynamics
The large guanosine triphosphatases (GTPases) in the dynamin fa-mily orchestrate the dynamic nature of mitochondria. Mitofusins (Mfn1and Mfn2) and optic atrophy factor 1 (OPA1) are the GTPases thatmediate the fusion of the outer and inner mitochondrial membrane,respectively, while the dynamin-related protein 1 (Drp1) is the mainGTPase effector for catalyzing the fission reaction.
Mitochondrial fusion contributes to the exchange of macro-molecules from two individual mitochondria; therefore resulting in anewly elongated fused mitochondrion. This new organelle displaysheterogeneous membrane potential and a diversified pool of proteins,metabolites and mtDNA (Chen et al., 2005). This phenomenon is im-portant to maximize ATP production under certain conditions such asexercise or starvation (Campos et al., 2017; Gomes et al., 2011;Rambold et al., 2011). The fusion of the first lipid bilayer surroundingthe organelle is achieved by the tethering of the membrane-anchoredmitofusins, which can occur through the formation of homo- (Mfn1-Mfn1 or Mfn2-Mfn2) or hetero-oligomers (Mfn1-Mfn2). Because of that,the ablation of either Mfn1 or Mfn2 leads to an aberrant mitochondrialmorphology in cell culture and results in embryonic lethality in mouse(Chen et al., 2003). Moreover, Mfn2 is enriched in mitochondria asso-ciated membranes (MAM) and plays an important role in endoplasmicreticulum-mitochondria tethering (de Brito and Scorrano, 2008). Mfn2deletion has a negative impact on the communication between thesetwo organelles, at least in part, by reducing calcium transfer from theendoplasmic reticulum to the mitochondria (Naon et al., 2016).
Mitofusins play an essential role in cardiac physiology. The absenceof either Mfn1 or Mfn2 results in progressive cardiomyopathy, char-acterized by pathological cardiac hypertrophy and impaired con-tractility properties (Chen and Dorn, 2013; Chen et al., 2011; Songet al., 2017). Mfn1 dysfunction contributes to the progression of heartfailure in rodents (Ferreira et al., 2019), whereas reduced Mfn2 levelsare associated with impaired skeletal muscle metabolism and insulinsensitivity in obesity and type 2 diabetes (Zorzano et al., 2009). Mfn2also plays a pivotal role in the nervous system. Impaired Mfn2 activity
is associated with Parkinson's disease (Chen and Dorn, 2013) and Alz-heimer's disease in rodents (Burte et al., 2015; Wang et al., 2009). Mfn2mutation also results in the inherited Charcot Marie Tooth disease(Zuchner et al., 2004), which can be rescued, at least in preclinicalstudies, by either rationally designed peptides or small molecule pep-tidomimetics that allosterically activates Mfn2 (Rocha et al., 2018).
The fusion between mitochondrial inner membranes is mediated bya single intermembrane space-localized GTPase – OPA1. Full inactiva-tion of OPA1 leads to embryonic lethality (Davies et al., 2007) andOPA1 mutations are associated with autosomal dominant optic atrophydisease (Delettre et al., 2000). The proper proteolytic cleavage of OPA1regulates mitochondrial number, cristae morphology and resistance toapoptosis (Delettre et al., 2001; Ishihara et al., 2006; Olichon et al.,2003). OPA1 processing – mainly driven by the proteases OMA1 andYME1L in a membrane potential dependent manner, generates long andshort OPA1 isoforms, favoring mitochondrial network elongation andfragmentation, respectively (Anand et al., 2014; Ehses et al., 2009;Head et al., 2009; Ishihara et al., 2006; Song et al., 2007). In thiscontext, excessive OPA1 cleavage (Wai et al., 2015) or OPA1 mutation(Chen et al., 2012) is sufficient to perturb mitochondrial function andmorphology leading to cardiomyopathy in mice. Of interest, reducedlevels of OPA1 are observed in heart failure patients (Chen et al., 2009).
Unlike mitochondrial fusion, fission segregates asymmetric portionsof mitochondria into spherical and smaller organelles. Once recruitedby specific adaptors anchored in the outer mitochondrial membrane(i.e. MFF – mitochondrial fission factor, Fis1 – mitochondrial fission 1protein), the cytosolic GTPase Drp1 binds to and orchestrates the con-striction of both membranes of the organelle (Gandre-Babbe and vander Bliek, 2008). This process is important during cell proliferation – byallowing cells to growth and be populated with new mitochondriaduring mitosis (Taguchi et al., 2007). Mitochondrial fragmentation isalso critical during mitophagy – by dispatching dysfunctional mi-tochondrial fragments to degradation in the lysosomes (Twig et al.,2008). Mitochondrial fragmentation can be triggered in response tonutrient excess (Toyama et al., 2016), and has been observed in me-tabolic (e.g. obesity and type II diabetes), neuromuscular and cardio-vascular diseases (Liesa and Shirihai, 2013; Wai and Langer, 2016).Clinical studies also revealed a positive association between Drp1 mu-tations and neurological disorders such as microcephaly and refractoryepilepsy (Vanstone et al., 2016; Waterham et al., 2007; Yoon et al.,2016).
5.2. Mitophagy
Mitophagy is a specialized category of autophagy that selectivelytargets mitochondria to degradation. This surveillance process helpspreventing the amplification of cellular damage by segregating andremoving sub-populations of depolarized (dysfunctional) mitochondria(Baechler et al., 2019; Youle and Narendra, 2011). Mitophagy is alsoinvolved in the elimination of paternal mitochondria during fertiliza-tion (Sato and Sato, 2011); therefore affecting mtDNA diversity andsusceptibility to inherited mitochondrial-related diseases.
During mitophagy, specific adaptor proteins – termed mitophagyadaptors (i.e. SQSTM1/p62, OPTN – Optineurin, NDP52 – also knownas CALCOCO2), work as cargo receptors to facilitate the recruitment ofdamaged mitochondria to the autophagosomes (Heo et al., 2015;Lazarou et al., 2015; Wong and Holzbaur, 2014). Different mechanismshave been evolved in mitophagy (for review see (Morales et al., 2019;Palikaras et al., 2018)). Briefly, dissipation of the mitochondrialmembrane potential stabilizes PINK1-Parkin interaction in the outermitochondrial membrane, thereby recruiting autophagosomal mem-branes to mitochondria and targeting them for lysosomal degradation(Narendra et al., 2008). There is also a Parkin-independent mitophagydriven by mitochondrial accumulation of FUNDC1, which in turn re-cruits autophagosome to mitochondria by direct interaction with LC3(Liu et al., 2012).
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Defective mitophagy plays a detrimental role in tissues highly de-pendent on mitochondrial metabolism (i.e. heart, brain and skeletalmuscle) (Ramesh et al., 2019). Mutations in PINK1 and Parkin genes(Corti et al., 2011) as well as Parkin inactivation (Dawson and Dawson,2014) lead to Parkinson's disease in humans. Moreover, genetic abla-tion of either PINK1 or Parkin results in neuronal loss and muscle de-generation in Drosophila and rodents (Billia et al., 2011; Clark et al.,2006; Park et al., 2006). These pathological phenotypes related to im-paired mitophagy are not limited to PINK-Parkin deficiencies. Muta-tions in mitophagy adaptor genes can lead to Crohn's disease
(Ellinghaus et al., 2013), primary open angle glaucoma (Rezaie et al.,2002) and amyotrophic lateral sclerosis (Maruyama et al., 2010).
Mitophagy is tightly connected to mitochondrial fusion-fission bal-ance (Chen and Dorn, 2013; Kageyama et al., 2014; Song et al., 2014,2015). During mitochondrial fission, an asymmetrical segregation re-sults in both smaller/depolarized and larger/polarized mitochondria;therefore favoring the elimination of depolarized mitochondria throughmitophagy. Therefore, mitochondrial fusion-fission balance and mito-phagy are critical in the context of both physiological and pathologicalconditions by directly affecting mitochondrial ATP production,
Table 1Clinical trials using mitochondrially-targeted and non-mitochondrially-targeted strategies that positively impacts mitochondrial function.
Main action Agent Diseases Phase References
Biogenesis Bezafibrate Mitochondrial FAO disorder Pilot Bonnefont et al. (2010)Mitochondrial myopathy II NCT02398201
Antioxidant effect Acipimox Type 2 Diabetes n.a. (Phielix et al., 2014; van de Weijer et al., 2015)ALC Chemotherapy-induced
neuropathyII (Hershman et al., 2013, 2014)
Diabetic neuropathy n.a. De Grandis and Minardi (2002)Neuropathic pain II Bianchi et al. (2005)
CoQ10 Amyotrophic lateral sclerosis II Kaufmann et al. (2009)Dyslipidemia III Zhang et al. (2018a)Heart failure II Mortensen et al. (2014)Huntington's disease III McGarry et al. (2017)Type 2 Diabetes III Zahedi et al. (2014)
Edaravone Amyotrophic lateral sclerosis III Writing and Edaravone (2017)EPI-743 Friedreich's ataxia II Zesiewicz et al. (2018)
Leigh syndrome II Martinelli et al. (2012)MELAS syndrome III Ahmed et al. (2018)Respiratory chain disease II NCT01370447
Idebenone Alzheimer's disease n.a. Thal et al. (2003)Friedreich's ataxia Pilot Hausse et al. (2002)Friedreich's ataxia III Meier et al. (2012)LHON II Rudolph et al. (2013)
MitoQ Alzheimer's disease II NCT00329056Cardiovascular function n.a. Adlam et al. (2005)Parkinson's disease n.a. Snow et al. (2010)
MTP-131 Heart failure I Daubert et al. (2017)LHON II NCT02693119Myocardial infarction II Gibson et al. (2016)
Omaveloxolone Friedreich's ataxia II Lynch et al. (2019)Resveratrol Alzheimer's disease II (Moussa et al., 2017; Turner et al., 2015)
Endometriosis-related pain n.a. Maia et al. (2012)Friedreich's ataxia II NCT03933163Metabolic syndrome n.a. Mendez-del Villar et al. (2014)
II NCT02114892Obesity n.a. (Clasen et al., 2014; Poulsen et al., 2013; van der Made et al., 2015)Type 2 Diabetes n.a. (Bhatt et al., 2012; Brasnyo et al., 2011)Diabetic neuropathy n.a. Hernandez-Ojeda et al. (2012)
Statins Diabetic neuropathy III (Hernandez-Ojeda et al., 2012; Villegas-Rivera et al., 2015)
ETC inhibition Thiazolidinedione Type 2 Diabetes n.a. Bogacka et al. (2005)II (Dormandy et al., 2005; Mazzone et al., 2006; Nissen et al., 2008; Wilcox
et al., 2007)
Gene therapy ND4-AAV LHON I (Feuer et al., 2016; Guy et al., 2017)
Mitochondrial transplantation Congenital heart disease Pilot Emani et al. (2017)
mPTP inhibition Cyclosporine A Cardiac arrest III NCT01595958Myocardial infarction Pilot Piot et al. (2008)
II-III Mewton et al. (2010)TRO19622 Neuropathic pain II NCT00876538
Spinal muscular atrophy II NCT02628743TRO40303 Myocardial infarction n.a. NCT01374321
II Atar et al. (2015)
NO precursor L-arginine MELAS syndrome II Rodan et al. (2015)
PDH inhibition Dichloroacetate MELAS syndrome II Savolainen (2006)
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oxidative stress and programed cell death (Shirihai et al., 2015).Therefore, therapies capable of maintaining a healthy mitochondrialpool by adjusting their size, shape, number, location and quality maybecome a valuable tool in a clinical perspective.
6. Therapies targeting mitochondria
Given the fact that mitochondrial dysfunction is not only a commonfeature of rare inherited mitochondrial diseases but also involved in thepathophysiology of many common disorders, it is not surprising that an
Table 2Preclinical studies using mitochondrially-targeted and non-mitochondrially-targeted strategies that positively impacts mitochondrial function.
Main action Agent Diseases/condition Model References
ALDH2 activation Alda-1 Acute inflammatory pain Rats/Mice Zambelli et al. (2014)Chronic neuropathic pain Mice Li et al. (2018)Ethanol-induced cardiomyopathy Mice Ueta et al. (2018)Heart failure Rats (Gomes et al., 2014, 2015)
Biogenesis AICAR Mitochondrial myopathy Mice Viscomi et al. (2011)Bezafibrate Respiratory chain disease Human cells Bastin et al. (2008)
Mice (Dillon et al., 2012; Viscomi et al., 2011)Nicotinamide riboside Alzheimer's disease Mice Gong et al. (2013)
Mitochondrial myopathy Mice Khan et al. (2014)
Antioxidant effect Coq10 Diabetic cardiomyopathy Mice De Blasio et al. (2015)Obesity/Type 2 Diabetes Mice Xu et al. (2017)
Edaravone Amyotrophic lateral sclerosis Mice Ito et al. (2008)Idebenone LHON Mice Heitz et al. (2012)MitoQ Alzheimer's disease Mice (Manczak et al., 2010; McManus et al., 2011)
DOX-induced cardiomyopathy Rats Chandran et al. (2009)Heart failure Rats Ribeiro Junior et al. (2018)I/R heart injury Rats Adlam et al. (2005)Obesity Mice (Fink et al., 2014, 2017)
MTP-131 Alzheimer's disease Mice Reddy et al. (2017)Amyotrophic lateral sclerosis Mice Petri et al. (2006)Heart failure Rats (Dai et al., 2013, 2014)Huntington's disease Mice Yin et al. (2016)Hypertrophic cardiomyopathy Mice Lu et al. (2017)Myocardial infarction Rats Shi et al. (2015)Neuropathic pain Mice Toyama et al. (2014)
N-acetylcysteine Diabetic neuropathy Rats Kamboj et al. (2010)NMN Type 2 Diabetes Mice Yoshino et al. (2011)PBN Neuropathic pain Mice Tanabe et al. (2009)
Rats (Gao et al., 2007; Kim et al., 2004)Resveratrol Alzheimer's disease Mice Karuppagounder et al. (2009)
Huntington's disease Mice Gerhardt et al. (2011)Obesity Mice (Baur et al., 2006; Lagouge et al., 2006)Parkinson's disease Mice (Gerhardt et al., 2011; Zhou et al., 2018)
Ru360 Opioid-induced pain Rats Lu et al. (2018)TEMPOL Inflammatory pain Rats Khattab (2006)
Mice Schwartz et al. (2008)Neuropathic pain Rats Fidanboylu et al. (2011)
Fusion-Fission balance Mdivi-1 Heart failure Mice Givvimani et al. (2012)Neuropathic pain Rats Ferrari et al. (2011)Parkinson's disease Mice Rappold et al. (2014)
Rats Bido et al. (2017)P110 Alzheimer's disease Mice Joshi et al. (2018a)
Amyotrophic lateral sclerosis Mice Joshi et al. (2018b)Huntington's disease Mice Guo et al. (2013)Myocardial infarction Rats Disatnik et al. (2013)
SAMβA Heart failure Rats Ferreira et al., 2019
MA-5 Mitochondrial diseases Human cells Matsuhashi et al., 2017Cilnidipine I/R heart injury Mice Nishimura et al. (2018)
Gene therapy Frataxin-AAV Friedreich's ataxia Mice (Gerard et al., 2014; Perdomini et al., 2014)ND4-AAV LHON Mice Yu et al. (2012)
Hypoxia 11% O2 Friedreich's ataxia Mice Ast et al. (2019)Leigh syndrome Mice Jain et al. (2016)
Mitochondrial transplantation I/R heart injury Pigs Kaza et al. (2017)Rabbits Masuzawa et al. (2013)
mPTP inhibition TRO19622 Neuropathic pain Rats (Bordet et al., 2008; Xiao et al., 2009)TRO40303 I/R heart injury Rats Schaller et al. (2010)
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intensive effort has been made for the development of new therapeuticstrategies targeting mitochondria. Overall, these strategies have beendesigned to preserve or improve mitochondrial function by modulatingkey components of mitochondrial biology, including bioenergetics,biogenesis, detoxifying enzymes, fusion-fission balance, mitophagy andUPRmt. Although only a small number of drugs targeting mitochondriahave entered clinical trials (Table 1), several potential targets haveemerged over the last years (Table 2). Here, we discuss some of thetherapeutic approaches that have been developed to repair mitochon-dria dysfunction in chronic degenerative diseases, such as cardiovas-cular, neurodegenerative and metabolic diseases, as well as in mi-tochondrial diseases.
6.1. Cardiovascular diseases
Cardiovascular diseases are the main cause of morbidity and mor-tality worldwide (Benjamin et al., 2019; Moons and Schuit, 2015). Acommon endpoint for many forms of cardiovascular diseases is thedevelopment of heart failure – a syndrome characterized by low cardiacoutput, dyspnea and exercise intolerance (Brum et al., 2011). Althoughthe mechanisms underlying the pathophysiology of cardiovasculardiseases are multiple and complex, available therapies mainly involvedrugs that reduce cardiac workload by targeting neurohumoral hyper-activation (e.g. beta-blockers and angiotensin-converting enzyme in-hibitors (Bartholomeu et al., 2008; Ferreira et al., 2008). These inter-ventions promote symptom relief; however, they only have marginalimpact on patient mortality and re-hospitalization rate (Bayeva et al.,2013; Kiyuna et al., 2018). Thus, discovering intracellular processesthat play a critical role in the establishment and progression of cardi-ovascular diseases is needed for developing better therapies.
Considering that cardiomyocytes have a high demand for ATPsynthesis and increased oxygen uptake rate, it is not surprising thatdisruption of mitochondrial homeostasis is a hallmark of cardiac dis-eases (Campos et al., 2016; Disatnik et al., 2013; Yogalingam et al.,2013). Multiple factors are involved in the loss of mitochondrialhomeostasis including dysfunctional bioenergetics, oxidative stress,calcium overload, accumulation of misfolded proteins and impairedmitochondrial biogenesis, fusion-fission balance and clearance (Bayevaet al., 2013; Campos et al., 2016; Rosca et al., 2013). Although it is notclear whether some of these factors are cause or consequence of cardiacinjury, they are considered potential targets for treating cardiovasculardiseases.
The use of antioxidants to prevent ROS-induced cardiac damage hasemerged as the prime therapy. Despite of promising results observed inpreclinical studies, antioxidants showed low efficacy in heart failurepatients (Hare et al., 2008; Heart Outcomes Prevention EvaluationStudy et al., 2000). This outcome reinforces the pitfalls of using anti-oxidants as a therapeutic approach since they neutralize both oxidativestress and redox signaling. Thus, an alternative approach that has beenproposed to enhance antioxidants effectiveness is targeting them tomitochondria. MitoQ is an antioxidant designed to act inside the mi-tochondria and it is currently being tested in clinical trial(NCT03586414 (Adlam et al., 2005)). Preclinical studies demonstratethat MitoQ reduces myocardium damage and improves cardiac functionin different animal models of cardiomyopathy (Adlam et al., 2005;Chandran et al., 2009; Ribeiro Junior et al., 2018).
Coenzyme Q10 (CoQ10) supplementation is a mitochondrially-un-targeted adjuvant intervention that indirectly affects mitochondrialoxidative stress. CoQ10 is a component of ETC that mediates electrontransport from complexes I and II to complex III. Its reduced form,ubiquinol, has an antioxidant effect inside the organelle (Kelso et al.,2001; Kiyuna et al., 2018). CoQ10 supplementation attenuates oxida-tive stress and cardiomyocyte remodeling in rodents with diabeticcardiomyopathy (De Blasio et al., 2015). Treatment of heart failurepatients with CoQ10 reduces the number of adverse cardiovascularevents and rates of hospitalization and mortality (Mortensen et al.,
2014). In addition, there are other antioxidant compounds with po-tential to treat cardiovascular diseases, including radical scavengers(Edaravone, XJB-5-131) and SOD mimetics (EUK8, M40403,Me2DO2A, MnTBPA) (Kiyuna et al., 2018).
Another attractive compound to treat cardiovascular diseases isMTP-131 (also known as SS31, Bendavia and Elamipretide). This is acell-permeable peptide that selectively targets the inner mitochondrialmembrane by association with cardiolipin, reducing ROS release andimproving ATP synthesis (Paradies et al., 2014; Szeto, 2014). MTP-131improves post-myocardial infarction cardiac function in rodents (Daiet al., 2013, 2014; Lu et al., 2017; Shi et al., 2015). MTP-131 has re-cently been tested in heart failure patients (NCT02388464 (Daubertet al., 2017)) and patients with myocardial infarction (NCT01572909 –EMBRACE). Despite of acceptable safety and tolerability in both clinicaltrials, MTP-131 failed to induce any improvement in the primaryendpoint– myocardial infarct size, in the EMBRACE trial (Gibson et al.,2016).
Inhibitors of mPTP opening are another class of mitochondrially-targeted compounds that are currently in clinical trials (NCT01595958,NCT01374321). Preliminary results in human patients suggest thatadministration of Cyclosporine A, at the moment of acute myocardialinfarction reperfusion, reduces infarct size (Mewton et al., 2010; Piotet al., 2008). TRO40303 is another inhibitor of mPTP opening thatpresent promising results in preclinical studies (Schaller et al., 2010).However, TRO40303 was not able to reduce cardiac injury in patientsundergoing revascularization after myocardial infarction (Trial Eu-draCT 2010-024616-33 (Atar et al., 2015)).
Over the last years, small molecules targeting mitochondria haveemerged as alternative approaches to treat cardiovascular diseases(Palaniyandi et al., 2010). One example is Alda-1 – an allosteric agonistof the mitochondrial-detoxifying enzyme ALDH2, which is involved inthe clearance of intracellular toxic aldehydes (e.g. 4-HNE) (Kiyunaet al., 2018; Zambelli et al., 2014). Alda-1 treatment reduces theoverload of reactive aldehydes; therefore improving mitochondrialbioenergetics and cardiac function in a heart failure rat model (Gomeset al., 2014, 2015). Alda-1 also protects ALDH2*2 knock-in mice fromethanol metabolism-induced cardiotoxicity (Ueta et al., 2018). Twoother compounds (MA-5 and Cilnidipine) that improve mitochondrialATP synthesis and re-establish morphology, respectively, are promisingcandidates to treat cardiac diseases (Matsuhashi et al., 2017; Nishimuraet al., 2018).
More recently, 2 peptides were rationally designed to inhibit ex-cessive mitochondrial fragmentation upon stress (P110 and SAMβA).Preclinical studies provide evidence that either (1) blocking mi-tochondrial fission by using the peptide P110 (a rationally-designedpeptide that inhibits Drp-1/Fis-1 interaction) or (2) re-establishingmitochondrial fusion activity by using SAMβA (a rationally-designedpeptide that Selectively Antagonizes Mfn1-βIIPKC Association) reducesischemia-reperfusion injury and improves cardiac function in heartfailure, respectively (Disatnik et al., 2013; Ferreira et al., 2011a, 2019;Givvimani et al., 2012).
Acute ischemia-reperfusion injury is characterized by an abruptmetabolic switch from glycolysis (ischemia) to oxidative phosphoryla-tion (reperfusion); therefore overwhelming mitochondrial quality con-trol pathways. Under this scenario, mitochondria become fragmentedand dysfunctional; therefore contributing to the long-term cardiac de-generation and consequent establishment of heart failure (Palaniyandiet al., 2010). The use of a selective inhibitor of fission machinery, P110,at the onset of reperfusion, decreases cardiac mitochondrial fragmen-tation and improves bioenergetics in three different models of ischemiareperfusion injury. P110 treatment also prevents the progression frompost-myocardial infarction-induced cardiac dysfunction to heart failurein rodents (Disatnik et al., 2013).
Blocking excessive mitochondrial fragmentation also plays a bene-ficial role in heart failure. Heart failure patients display two inter-connected processes: increased βIIPKC (βII protein kinase C) activity
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(Ferreira et al., 2012) and accumulation of fragmented mitochondria(Chaanine et al., 2019). During heart failure, βIIPKC accumulates onthe mitochondrial outer membrane and phosphorylates Mfn1; thereforeresulting in partial loss of its GTPase activity and accumulation offragmented and dysfunctional mitochondria (Ferreira et al., 2019).Under this scenario, a sustained treatment of heart failure rats withSAMβA, a short peptide that selectively blocks excessive Mfn1-βIIPKCinteraction, is sufficient to rescue mitochondrial morphology, bioener-getics and improve cardiac contractility properties (Ferreira et al.,2019). These findings suggest SAMβA as a potential treatment for heartfailure patients with reduced ejection fraction (HFrEF). SAMβA mightalso have a beneficial impact in heart failure patients with preservedejection fraction (HFpEF), a disease also characterized by accumulationof fragmented mitochondria (Chaanine et al., 2019).
Mitochondrial transplantation is another promising approach totreat mitochondrial dysfunction in cardiac diseases. The treatmentconsists of autologous injection of healthy mitochondria, harvestedfrom an unaffected tissue (i.e. skeletal muscle), into the ischemic heart(Emani et al., 2017). Transplanted mitochondria protect the heartagainst ischemia-reperfusion injury in both rabbit and porcine animalmodels (Kaza et al., 2017; Masuzawa et al., 2013). Overall, mitochon-drial transplantation increases oxygen consumption and ATP produc-tion; therefore resulting in better cardiac contractility properties. Thisnovel technique has been successfully applied in pediatric patients withcongenital heart disease. All treated patients displayed improved car-diac function without adverse events such as arrhythmia, intra-myo-cardial hematoma or scarring (Emani et al., 2017). These results suggestmitochondrial transplantation as a promising therapy for the treatmentof cardiovascular disease; however, multicenter randomized trials arestill required.
Finally, there are other emerging, but not mitochondrially-targeted,strategies to counteract mitochondria dysfunction in cardiovasculardiseases such as activators of AMPK (Gelinas et al., 2018), UPRmt(Smyrnias et al., 2019)) and guanylate cyclase receptor (i.e. Vericiguat(Breitenstein et al., 2017)).
6.2. Metabolic syndrome, obesity and type 2 diabetes
Metabolic syndrome is a public health problem that affects millionsof people worldwide (Saklayen, 2018). This syndrome arises from acombination of risk factors including obesity, dyslipidemia, elevatedplasma glucose levels and hypertension (Murphy and Hartley, 2018;Saklayen, 2018). The clinical management of metabolic diseases pri-marily involves the mitigation of risk factors including changes inlifestyle, drug therapy and bariatric surgery (Grundy et al., 2005;Murphy and Hartley, 2018). Since these interventions mostly promotesymptoms relief, there is a need for more effective therapies to treat, orat least, prevent the progression of metabolic syndrome.
Mitochondrial quality control-related processes are impaired inmetabolic diseases. Diabetic and obese patients display dysfunctionalskeletal muscle β-oxidation of fatty acids, bioenergetics, biogenesis andexcessive oxidative stress (Mootha et al., 2003; Rong et al., 2007;Sorrentino et al., 2018). In addition, disruption of mitochondrial fusion-fission balance and mitophagy are observed in these patients (Anelloet al., 2005; Kelley et al., 2002; Seillier et al., 2015). These findingspoint out mitochondrial dysfunction as a critical player in the patho-physiology of metabolic diseases and highlight the therapeutic value ofstrategies targeting defective mitochondria under those conditions.
Metformin is a widely used drug for the treatment of type 2 dia-betes. However, its mechanism of action remains to be fully elucidated.Metformin has been reported to inhibit mitochondrial ETC complex I(Owen et al., 2000); therefore increasing ADP:ATP ratio and inducingAMPK activation, which then suppress hepatic gluconeogenesis (Foretzet al., 2014; Zhou et al., 2001). Metformin also inhibits hepatic gluco-neogenesis in a complex I-independent manner where its glucose-low-ering effects are related to the inhibition of the mitochondrial glycerol-
3-phosphate dehydrogenase – a key redox shuttle enzyme that reducesthe conversion of lactate and glycerol to glucose, and decreased hepaticgluconeogenesis (Madiraju et al., 2014, 2018).
Thiazolidinedione, a class of PPAR agonist also known as rosigli-tazone and pioglitazone, is capable of reducing plasma glucose levels byimproving hepatic and peripheral glucose utilization in diabetic pa-tients (Diamant and Heine, 2003). The beneficial effects of thiazolidi-nedione in type 2 diabetes are related to improved mitochondrial bio-genesis (Bogacka et al., 2005) and ETC complex I inhibition (Brunmairet al., 2004; Garcia-Ruiz et al., 2013). Phase III clinical trials demon-strate a positive effect of pioglitazone in lowering the risk of cardio-vascular events in type 2 diabetic patients (NCT00174993 (Dormandyet al., 2005; Wilcox et al., 2007), NCT00225264 (Mazzone et al., 2006),NCT00225277 (Nissen et al., 2008)).
Resveratrol, a natural polyphenolic compound mainly found ingrapes, is another molecule tested in metabolic diseases. Resveratrol isnot a mitochondrially-targeted compound, but it has some indirectmitochondrial effects including reduction of mitochondrial oxidativestress and induction of mitochondrial biogenesis through the activationof PGC1α. Pre-clinical studies demonstrate that resveratrol protectsrodents against diet-induced obesity and insulin resistance (Baur et al.,2006; Lagouge et al., 2006). However, resveratrol fails to improve in-sulin sensitivity and metabolic outcome in obese patients(NCT01364961 (van der Made et al., 2015); NCT01150955 (Clasenet al., 2014; Poulsen et al., 2013). In another randomized, double-blindand placebo-controlled clinical trial, resveratrol supplementation re-duced weight, fat mass and hyperinsulinemia in patients with metabolicsyndrome (Mendez-del Villar et al., 2014). Taken together, these resultssuggest that resveratrol may be an adjuvant in the treatment of mi-tochondrial dysfunction in metabolic syndrome and type 2 diabetes.
Supplementation with NAD + precursors is another adjuvant ap-proach tested in metabolic syndrome. Enhancing NAD + availabilitythrough the administration of nicotinamide mononucleotide improvesinsulin tolerance in diet-induced type 2 diabetes in rodents (Yoshinoet al., 2011). Similar results were observed in a multicenter, rando-mized and crossover trial conducted in type 2 diabetic patients re-ceiving another NAD + precursor – Acipimox (NCT00943059 (Phielixet al., 2014; van de Weijer et al., 2015)). NAD + precursors are notmitochondrially-targeted strategies, but they have indirect mitochon-drial effects such as reduced mitochondrial oxidative stress and im-proved mitochondrial function in skeletal muscle from type 2 diabeticpatients (Phielix et al., 2014; van de Weijer et al., 2015).
Finally, the mitochondrially-targeted antioxidant MitoQ has beenrecently tested in metabolic diseases. MitoQ attenuates weight gain andameliorates hepatic dysfunction in obese rodents (Fink et al., 2014,2017). Similarly, administration of CoQ10 mitigates the progression ofobesity and type 2 diabetes in mice (Xu et al., 2017). CoQ10 has beentested in Phase III clinical trials in patients with dyslipidemia(NCT02407548 (Zhang et al., 2018b)) and type 2 diabetes(IRCT138806102394N1 (Zahedi et al., 2014)). CoQ10 amelioratesmultiple cardiovascular risk factors in patients with dyslipidemia(Zhang et al., 2018b) and improves glycemic control in type 2 diabeticpatients (Zahedi et al., 2014). Overall, these studies suggest that mi-tochondrially (un)targeted therapies aiming to re-establish mitochon-drial function are promising strategies for the treatment of metabolicsyndrome, obesity and type 2 diabetes.
6.3. Neurodegenerative diseases
Neurodegenerative diseases, such as Alzheimer, Huntington andParkinson are characterized by progressive dysfunction and loss ofanatomically or physiologically related neuronal systems (Lin and Beal,2006). Neurodegenerative diseases affect millions of people worldwideand their prevalence keep rising as the mean age of population in-creases (Kiaei, 2013). Considering the current lack of effective therapiesin counteracting neurodegeneration, the identification of critical
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mechanisms underlying such pathologies as well as the development ofnovel therapeutic approaches represent an unmet clinical need.
Mitochondrial dysfunction plays a central role in neurodegenerativediseases (Andreux et al., 2013; Johri and Beal, 2012; Lin and Beal,2006; Mao and Reddy, 2010). Impaired mitochondrial bioenergetics,oxidative stress (Nunomura et al., 2001), mitochondrial DNA mutations(Coskun et al., 2004; De Coo et al., 1999), disruption of mitochondrialproteostasis (Sorrentino et al., 2017), dysfunctional mitochondrial dy-namics (Cho et al., 2009) and defective mitophagy (Tang et al., 2006)are constantly associated with the establishment and progression ofneurodegenerative diseases. Therefore, the development of interven-tions capable of improving mitochondrial functionality may have atherapeutic effect against neurodegenerative diseases.
The use of mitochondrially-targeted antioxidants has emerged as apotential therapy to treat neurodegenerative diseases. MitoQ attenuatesoxidative stress, synaptic loss and amyloid beta peptide accumulation,which is associated with preserved cognitive function in a rodent modelof Alzheimer's disease (Manczak et al., 2010; McManus et al., 2011).The effectiveness of MitoQ in improving Alzheimer's disease outcomewas evaluated in a Phase II clinical trial (NCT00329056), but the resultshave not been released yet. In another clinical trial, MitoQ failed toslow down the progression of Parkinson's disease (NCT03514875 (Snowet al., 2010)). Similarly, the treatment with CoQ10 showed no bene-ficial effects in patients with amyotrophic lateral sclerosis(NCT00243932 (Kaufmann et al., 2009)) and Huntington's disease(NCT00608881 (McGarry et al., 2017)). Likewise, the CoQ10 analogIdebenone (also known as CV-2619) failed to attenuate the cognitivedecline in patients with Alzheimer's disease (Thal et al., 2003).
The non mitochondrially-targeted free radical scavenger Edaravone(also known as MCI-186) in another therapeutic approach tested inneurodegenerative diseases with positive effects in mitochondrialfunction. Edaravone attenuates the progression of amyotrophic lateralsclerosis by slowing down motor neuron degeneration in rodents (Itoet al., 2008). Likewise, Edaravone treatment improves the clinical scoreof early stage-amyotrophic lateral sclerosis patients in a randomizedand double-blind study (NCT01492686 (Writing and Edaravone,2017)). The effectiveness of Edaravone therapy in advanced stage-amyotrophic lateral sclerosis remains to be determined. More recently,the mitochondrially-targeted antioxidant MTP-131 exhibited positiveresults in reducing synaptic damage in Huntington's disease (Yin et al.,2016), decreasing amyloid beta peptide accumulation in Alzheimer'sdisease (Reddy et al., 2017) and improving motor performance inamyotrophic lateral sclerosis (Petri et al., 2006).
Resveratrol is another compound tested in neurodegenerative dis-eases. Overall, resveratrol attenuates the symptoms of Parkinson's,Huntington's and Alzheimer's disease in rodents (Gerhardt et al., 2011;Karuppagounder et al., 2009; Zhang et al., 2018a). Results from a PhaseII clinical trial conducted in Alzheimer's patients suggest that Resver-atrol supplementation is safe, well-tolerated and induces an adaptiveimmune response that may improve brain resilience to amyloid de-position (NCT01504854 (Moussa et al., 2017; Turner et al., 2015)).Another ongoing clinical trial evaluates the benefits of resveratrolsupplementation in improving the neuronal bioenergetics profile inHuntington's disease patients (NCT02336633). A randomized, multi-center, double-blind study is still needed to determine the impact ofresveratrol on cognitive and functional improvements in patients withdegenerative diseases. Overall, these results showing either beneficialor neutral effects of targeting oxidative stress in neurodegenerativediseases reinforce the notion that antioxidants must work in a time-,dose- and tissue-dependent manner (without affecting the redox sig-naling).
Finally, emerging therapies targeting mitochondrial quality controlincluding mitochondrial dynamics, clearance and, more recently, mi-tochondrial release have been recently tested in neurodegenerativediseases (Itoh et al., 2013; Joshi et al., 2019). Inhibition of mitochon-drial fragmentation, by using the peptide P110, slows down the
progression of Huntington's disease (Guo et al., 2013), amyotrophiclateral sclerosis (Joshi et al., 2018b) and Alzheimer's disease (Joshiet al., 2018a) in rodents. Likewise, blocking excessive mitochondrialfission through the administration of Mdivi-1 attenuates mitochondrialdysfunction and oxidative stress in a rodent model of Parkinson's dis-ease, which is associated with neuroprotection and improved motorfunction (Bido et al., 2017; Rappold et al., 2014). Another attractiveapproach tested in preclinical studies is the use of nicotinamide riboside– a NAD + precursor. Nicotinamide riboside supplementation results inincreased expression of PGC-1α-modulated genes, reduced amyloidaggregation and better cognitive function in a mouse model of Alz-heimer's disease (Gong et al., 2013; Sorrentino et al., 2017). Clinicalstudies testing the safety and effectiveness of either blocking excessivemitochondrial fission or increasing NAD + levels in neurodegenerativediseases are needed.
6.4. Targeting mitochondria for pain relief
Chronic pain is a growing epidemiologic problem affecting abouttwo billion people worldwide (Goldberg and McGee, 2011). Pain ischaracterized by the transmission of the noxious information from theperiphery to the central nervous system, where it is processed and in-terpreted as pain. Both neuropathic and chronic inflammatory painmodels have been lately associated with neuronal mitochondrial dys-function including impaired bioenergetics, calcium overload, oxidativestress and aldehydic burden (Flatters, 2015; Zambelli et al., 2014).
ROS and RNS are associated with different chronic pain conditions(Grace et al., 2016; Salvemini et al., 2011). Mitochondrially-untargetedantioxidants have been tested in pain (Pisano et al., 2003; Zheng et al.,2011, 2012). PhenylN-tert-butylnitrone (PBN) – a nonspecific ROSscavenger, inhibits hypersensitivity evoked by nerve injury (Gao et al.,2007; Kim et al., 2004; Tanabe et al., 2009), inflammation (Schwartzet al., 2008; Tanabe et al., 2009) and chemotherapy-induced neuro-pathy in rodents (Kim et al., 2010). Similarly, TEMPOL (4-Hydroxy-2,2,6, 6-tetramethylpiperidine-1-oxyl) reverses chemotherapy-inducedpain when administered prophylactically (Fidanboylu et al., 2011), andinhibits nerve injury- or inflammation-induced hypersensitivity whenadministered therapeutically (Khattab, 2006; Lee et al., 2007; Schwartzet al., 2008; Tanabe et al., 2009; Wang et al., 2004). When administeredtogether, TEMPOL and PBN attenuate cancer-induced bone pain bysuppressing neuroinflammation in the sciatic nerve (Zhou et al., 2018).Finally, N-acetylcysteine and Acetyl-L-carnitine (ALC) inhibit thermalhyperalgesia in diabetic neuropathy and hypersensitivity in che-motherapy-induced pain in rats, respectively (Kamboj et al., 2010).
Overall, these preclinical studies demonstrate a beneficial role ofmitochondrially-untargeted antioxidants to treat pain. However, theantioxidant benefits for human pain conditions are still controversial. APhase II clinical trial does not support the use of ALC as a treatment forchemotherapy-induced neuropathic pain (Hershman et al., 2013,2014). Another independent study suggests that ALC alleviates symp-toms associated with diabetic neuropathy in humans (De Grandis andMinardi, 2002; Sima et al., 2005). Likewise, diabetic neuropathic pa-tients display improved pain scores and nerve conduction parameterswhen treated with either statins, which presumably have some anti-oxidant effects, (NCT02129231 (Villegas-Rivera et al., 2015)) or ubi-quinone (Hernandez-Ojeda et al., 2012). The ubiquinone effects areassociated with reduced oxidative stress (Hernandez-Ojeda et al.,2012).
Aldehydes also play an important role in the pathophysiology ofpain (Trevisani et al., 2007). Therefore, pharmacological interventionscapable of improving the catalytic activity of enzymes involved in theclearance of aldehydes generated during mitochondrial dysfunctionmight become a useful strategy to tackle pain. In fact, the re-estab-lishment of aldehyde clearance by Alda-1 (ALDH2 activator) is suffi-cient to block inflammatory pain-like behavior in rodents (Zambelliet al., 2014). As a proof of concept, a knock-in mouse model mimicking
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the human ALDH2 inactivating point mutation (E504K), the mostcommon mutation worldwide (~540 million people), is more sensitiveto painful stimuli compared with wild-type. Indeed, Alda-1 neutralizesthe elevated nociception observed in mice carrying the ALDH2 (E504K)mutation. This response is associated with improved ALDH2 activityand less reactive aldehyde accumulation at the insult site (includingacetaldehyde and 4-HNE). The beneficial effects of Alda-1 have alsobeen reported in neuropathic pain models (Li et al., 2018). Overall,these preclinical studies suggest ALDH2 as a new molecular target forpain control. However, clinical studies are required to test both safetyand efficacy of such interventions in humans.
Inhibitors of mPTP opening are another class of mitochondrially-targeted compounds used in pain research. Olesoxime (TRO19622) is acholesterol-like compound that directly binds to two components of themPTP: the voltage-dependent anion channel and the translocator pro-tein 18 kDa. Olesoxime accumulates in the mitochondria and preventsoxidative stress-induced mPTP opening. Preclinical studies demonstratethat Olesoxime reduces pain in chemotherapy- and diabetes-inducedneuropathy in rodents (Bordet et al., 2008; Xiao et al., 2009). A phase 2clinical trial using Olesoxime in patients treated with chemotherapywas completed in 2016, but the results have not been released yet(NCT00876538). Another clinical trial using Olesoxime in patients withspinal muscular atrophy was suspended due to disappointing clinicaltrial results (NCT02628743).
Another mitochondrially-related strategy to treat pain is the use ofcompounds that block excessive neuronal mitochondrial fragmentationduring pain. Blocking excessive mitochondrial fission by using Midvi-1(which also directly inhibits mitochondrial complex I activity) attenu-ates pain-like behavior in two different models of neuropathy: HIV/AIDS antiretroviral and chemotherapy (Ferrari et al., 2011). Thesefindings open up a new avenue for testing other selective moleculescapable of counteracting the excessive mitochondrial fragmentation inpain such as the peptide P110, which blocks excessive mitochondrialfragmentation.
The tumor suppressor p53 is another promising target to treat pain.Under stress conditions, p53 translocates to mitochondria, mediatesmitochondrial outer membrane permeabilization and consequent re-lease of apoptosis-promoting proteins like cytochrome c (Chipuk et al.,2004; Mihara et al., 2003). Pifithrin-μ, a small molecule that inhibitsmitochondrial p53 accumulation, prevents the development of che-motherapy-induced nociception (Krukowski et al., 2015). Similarly,minoxidil, a compound with high selectivity for mitochondrial ATP-dependent K+ channel (mitoKATP) (Sato et al., 2004) and FDA ap-proved drug for treating hypertension and alopecia, alleviates bothchemotherapy-induced peripheral neuropathy and neuroinflammationin rodents (Chen et al., 2017). However, controlled clinical trials testingthe effectiveness of these compounds are still necessary. Finally, paincan be paradoxically triggered by opioids, such as morphine, and mi-tochondria may participate in opioid-induced hyperalgesia. In this re-gard, pretreatment with Ru360, a specific mitochondrial calcium uni-porter antagonist, remarkably attenuates opioid-induced pain behaviorin mice (Lu et al., 2018).
6.5. Mitochondrial diseases
Mitochondrial disease is a broad term to describe a pathologicalcondition attributed to loss-of-function mutations in mitochondrialproteins encoded by mitochondrial or nuclear genes. In general, theseinborn errors result in abnormal oxidative phosphorylation and defec-tive ATP production. Considering that tissues like nervous system,skeletal muscle and heart are highly oxidative, it is somehow expectedthat some mitochondrial diseases have pronounced and devastatingphenotypes (Niyazov et al., 2016). For example, MELAS syndrome givesrise to mitochondrial encephalomyelopathy, lactic acidosis and stroke-like episodes (El-Hattab et al., 1993), while the primary features ofFriedreich's ataxia include progressive loss of coordination and
ambulation, muscle weakness and cardiomyopathy (Gomes and Santos,2013). Therefore, their clinical and genetic heterogeneity along withunder-diagnosis in clinical practice make it difficult not only to estimatethe true prevalence of mitochondrial diseases, but also to develop ef-fective therapies (El-Hattab et al., 2017; Niyazov et al., 2016; Pfefferet al., 2012).
To date, there is no cure to any mitochondrial disease or approvedtherapies to relief the symptoms. Based on the rationale that mi-tochondrial dysfunction-induced ROS accumulation might be involvedin the pathophysiology of mitochondrial diseases, several interventionstargeting mitochondrial oxidative stress have been tested (Hayashi andCortopassi, 2015). Working as a CoQ10 analog, Idebenone enhancesmitochondrial function and induces protection against lipid peroxida-tion (Gueven et al., 2015). Idebenone also protects against loss of colorvision in Leber's Hereditary Optic Neuropathy patients (LHON – aninherited disease triggered by mutations in ETC Complex I,NCT00747487 (Rudolph et al., 2013)) and retinal damage in a mousemodel of LHON (Heitz et al., 2012). However, the benefits of idebenoneon neurological symptoms in mitochondrial diseases are still incon-sistent.
Idebenone treatment reduces cardiac hypertrophy in Friedreich'sataxia patients (Hausse et al., 2002). However, no significant effectswere found in a Phase III clinical trial (NCT00537680 6 months,NCT00697073 12 months (Meier et al., 2012)). Because Friedreich'sataxia is associated with decreased NRF2 activity, omaveloxolone (RT-408) has been tested in those patients (Reisman et al., 2019). Omave-loxolone is a non mitochondrially-targeted synthetic activator of NRF-2capable of increasing the transcription of antioxidants genes. Pre-liminary results of the ongoing Phase II clinical trial (NCT02255435)demonstrate a dose-dependent improvement in neurological function.However, a few adverse symptoms (e.g. upper respiratory tract infec-tion and headache) along with significant placebo effects are also noted(Lynch et al., 2019). Finally, a Phase II clinical trial failed to demon-strate idebenone efficacy in patients with MELAS syndrome(NCT00887562 (Ahmed et al., 2018)).
Following the antioxidant rationale strategy, other drugs have beenrecently tested in mitochondrial diseases. A single-arm clinical trial, inwhich all the children with Leigh syndrome received the EPI-743 – asmall molecule able to improve the redox status by modulating oxi-doreductase activity, reported clinical improvements and prevention ofthe disease progression (Martinelli et al., 2012). Unlike, a double blind,randomized and controlled trial of EPI-743 in Friedreich's ataxia did notfind clinical improvements following 6 months of treatment(NCT01728064 (Zesiewicz et al., 2018)). Other ongoing Phase II clin-ical trials are testing EPI-743 in mitochondrial respiratory chain dis-eases (NCT01370447), Resveratrol in Friedreich's ataxia(NCT03933163) and MTP-131 in LHON (NCT02693119).
More recently, chronic hypoxia has been validated as a promisingtherapy in mitochondrial diseases. Either genetic or pharmacologicalactivation of hypoxia response is protective against mitochondrialtoxicity (Jain et al., 2016). Moreover, animal models of Leigh syndrome(Jain et al., 2016) and Friedreich's ataxia (Ast et al., 2019) exhibitimprovements in lifespan, neuromuscular function and reduced diseasebiomarkers upon chronic exposure to hypoxic environment (11% O2
compared to 21% O2 in breathing air) (Jain et al., 2016).Considering the fact that increasing mitochondrial mass usually
contributes to improved bioenergetics (Kelly and Scarpulla, 2004), in-ducers of mitochondrial biogenesis have been tested in mitochondrialdisorders. Bezafibrate – a PPAR agonist, stimulates mitochondrial bio-genesis and increases oxidative phosphorylation in human cells car-rying mutations in ETC subunits (Bastin et al., 2008). However, noclinical improvements are observed in animal models of mitochondrialdiseases (i.e. ETC complex IV deficiency (Dillon et al., 2012; Viscomiet al., 2011)). Of interest, a pilot trial testing bezafibrate in patientswith a rare mitochondrial fatty acid oxidation disorder, characterizedby skeletal muscle pain and weakness, shows improvement in clinical
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outcomes (Bonnefont et al., 2010).Other non mitochondrially-targeted interventions such as activation
of AMPK by AICAR (Viscomi et al., 2011) or increase NAD + levels bynicotinamide riboside (Khan et al., 2014) were recently tested in mi-tochondrial diseases. AICAR and nicotinamide riboside induce mi-tochondrial biogenesis and UPRmt response, respectively (Mouchiroudet al., 2013; Toyama et al., 2016), Overall, these interventions delaydisease progression in a mouse model of mitochondrial myopathy(Mouchiroud et al., 2013; Toyama et al., 2016). The effectiveness ofnicotinamide riboside supplementation is currently being tested in pa-tients with mitochondrial diseases (NCT03432871).
Despite the variety of loss-of-function mutations in mitochondrialgenes, the major sites are well known. In that sense, the most recent andattractive developing therapies target the mutation itself, rather thanaddressing the symptoms. Gene therapy – generally described as anapproach that delivers engineered viruses carrying a therapeutic gene,allows the replacement of a mutated gene by its functional copy (Jangand Lim, 2018; Tuppen et al., 2010). Successful delivery of the humanfrataxin gene –which is reduced in Friedreich's ataxia patients, im-proves the disease outcome in preclinical models. Gene therapy-in-duced increased levels of frataxin reverses severe cardiomyopathy(Perdomini et al., 2014), improves neuromuscular activity and in-creases lifespan in preclinical models of Friedreich's ataxia (Gerardet al., 2014).
Positive results have also been achieved in LHON disease, which isoften caused by mutations in the mtDNA gene encoding ND4 – and ETCcomplex I subunit (Howell, 1997). Injection of the functional homologof a defective ND4 gene into the LHON rodent eye restores ATP levelsand suppresses both optic atrophy and visual loss (Yu et al., 2012). Anopen-label clinical trial (NCT02161380) is currently testing the effec-tiveness of ND4 gene therapy in improving LHON outcome. The pre-liminary data suggests visual acuity improvements without adverseeffects in LHON patients (Feuer et al., 2016; Guy et al., 2017).
7. Summary and perspectives
Mitochondria play critical role in bioenergetics, redox balance, ionhomeostasis, and cell death. More recently, mitochondria have beenclassified as unique nodes/transducers as well as multi-effector playersthat directly control a range of intracellular processes involved in theestablishment and/or progression of several diseases. Under this sce-nario, extensive efforts have been made over the last years to under-stand the most critical mitochondrial processes involved in degen-erative diseases. As a consequence, a large amount of knowledge hasbeen generated over the last years regarding the role of mitochondrialbioenergetics, redox signaling, biogenesis, morphology, surveillanceand clearance in health and disease. More recently, many new mi-tochondrial targets have been tested as druggable entities; therefore,bringing up a new avenue for the development of pharmacological andnon-pharmacological interventions capable of restoring mitochondrialfunction. Overall, these preclinical studies present very positive results;however, we still miss positive clinical trial results to pursue mi-tochondrial therapies as an effective intervention to treat diseases.Moreover, future research focusing on the critical molecular eventsinvolved in mitochondrial biology is needed to develop better phar-macological interventions.
Acknowledgments
This work was supported by Fundação de Amparo à Pesquisa doEstado de São Paulo (FAPESP) #2017/16694-2, #2017/16071-5,#2017/16540-5, #2017/24836-1, #2018/19332-7, #2018/18627-3and CEPID FAPESP #2013/07937-8, Conselho Nacional de Pesquisa eDesenvolvimento – Brasil (CNPq) #407743/2018-9, #307934/2018-7,#303281/2015-4 and #407306/2013-7, and Coordenação deAperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) Finance
Code 001.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.org/10.1016/j.mam.2019.100836.
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