Advanced Emergency Nursing Journal Vol. 31, No. 1, pp. 54–62 Copyright c 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins Mitochondria The Hemi of the Cell Elizabeth M. Cusimano, BSN, RN ; Amanda R. Knight, BA ; Joyce G. Slusser, PhD ; Richard L. Clancy, PhD ; Janet D. Pierce, DSN, ARNP, CCRN Abstract There are many organelles within a cell, each with individual responsibilities required for life. Of these organelles, the mitochondria are the hemi of the cell, producing the energy necessary for cell function. Reactive oxygen species can cause mitochondrial dysfunction and contribute to many diseases often seen in emergency departments. When reactive oxygen species are produced, the mitochondria undergo functional and structural changes causing the release of cytochrome c. Cy- tochrome c is responsible for activating apoptotic pathways leading to cell death. Apoptosis, or programmed cell death, is needed to maintain homeostasis in the body; however, when this occurs prematurely by an increase in reactive oxygen species production, many pathological conditions can occur. Clinicians in emergency departments caring for patients with different diseases should consider that the mitochondria may play an important role in patients’ recovery. For instance, my- ocardial infarctions and burns are two examples of altered physiologic states that play a role in mitochondrial dysfunction. Awareness of the different treatments that target the mitochondria will prepare emergency department clinicians to better care for their patients. Key words: apoptosis, free radicals, mitochondria O XIDATIVE STRESS is involved with many diseases such as emphysema, myocardial infarction (MI), and stroke (Anderson, Seed, Ou, & Harris, 1999; Hill & Singal, 1996; Leinonen et al., 2000). From the School of Nursing (Mss Cusimano and Knight and Dr Pierce) and Medical Center (Drs Slusser and Clancy), the University of Kansas, Kansas City. This project was sponsored by the TriService Nursing Re- search Program (HU0001-08-1-TS08); however, the in- formation or content and conclusions do not necessar- ily represent the official position or policy of, nor should any official endorsement be inferred by, the TriService Nursing Research Program, the Department of Defense, or the U.S. Government. Corresponding author: Amanda R. Knight, BA, Uni- versity of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160 (e-mail: [email protected]). Oxidative stress occurs when the production of free radicals in the body exceeds the ability to eliminate them or by a reduction in antioxidants. Free radicals react with dif- ferent organelles of the cell, particularly the mitochondria. The mitochondria are often forgotten about in nursing practice yet are an essential source of energy and metabolism and play a role in several different disease processes. Reactive oxygen species (ROS) are free radicals that affect the mitochondria. When there is an increase in ROS formation, cellular damage often occurs resulting in dysfunction to the mitochondria (Murphy & Smith, 2000; Pieczenik & Neustadt, 2007). The damaged mitochondria trigger a release of cytochrome c through the mitochondrial 54
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Advanced Emergency Nursing JournalVol. 31, No. 1, pp. 54–62
Elizabeth M. Cusimano, BSN, RN;Amanda R. Knight, BA;Joyce G. Slusser, PhD;Richard L. Clancy, PhD;Janet D. Pierce, DSN, ARNP, CCRN
AbstractThere are many organelles within a cell, each with individual responsibilities required for life. Ofthese organelles, the mitochondria are the hemi of the cell, producing the energy necessary forcell function. Reactive oxygen species can cause mitochondrial dysfunction and contribute to manydiseases often seen in emergency departments. When reactive oxygen species are produced, themitochondria undergo functional and structural changes causing the release of cytochrome c. Cy-tochrome c is responsible for activating apoptotic pathways leading to cell death. Apoptosis, orprogrammed cell death, is needed to maintain homeostasis in the body; however, when this occursprematurely by an increase in reactive oxygen species production, many pathological conditionscan occur. Clinicians in emergency departments caring for patients with different diseases shouldconsider that the mitochondria may play an important role in patients’ recovery. For instance, my-ocardial infarctions and burns are two examples of altered physiologic states that play a role inmitochondrial dysfunction. Awareness of the different treatments that target the mitochondria willprepare emergency department clinicians to better care for their patients. Key words: apoptosis,free radicals, mitochondria
OXIDATIVE STRESS is involved withmany diseases such as emphysema,myocardial infarction (MI), and
From the School of Nursing (Mss Cusimano and Knightand Dr Pierce) and Medical Center (Drs Slusser andClancy), the University of Kansas, Kansas City.
This project was sponsored by the TriService Nursing Re-search Program (HU0001-08-1-TS08); however, the in-formation or content and conclusions do not necessar-ily represent the official position or policy of, nor shouldany official endorsement be inferred by, the TriServiceNursing Research Program, the Department of Defense,or the U.S. Government.
Corresponding author: Amanda R. Knight, BA, Uni-versity of Kansas Medical Center, 3901 Rainbow Blvd,Kansas City, KS 66160 (e-mail: [email protected]).
Oxidative stress occurs when the productionof free radicals in the body exceeds theability to eliminate them or by a reductionin antioxidants. Free radicals react with dif-ferent organelles of the cell, particularly themitochondria. The mitochondria are oftenforgotten about in nursing practice yet are anessential source of energy and metabolismand play a role in several different diseaseprocesses. Reactive oxygen species (ROS)are free radicals that affect the mitochondria.When there is an increase in ROS formation,cellular damage often occurs resulting indysfunction to the mitochondria (Murphy &Smith, 2000; Pieczenik & Neustadt, 2007).The damaged mitochondria trigger a releaseof cytochrome c through the mitochondrial
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pores (Yang et al., 1997). Once the cy-tochrome c is released, this commits the cellto die (Green & Reed, 1998). Cytochromec is involved in the signaling of apoptosis,and when released prematurely, the result isoften disease.
Programmed cell death (apoptosis) hasbeen linked to many pathophysiologic statesand is an important issue in clinical prac-tice and research (Reed, 2002). This articlereviews the structure and function of differ-ent organelles, particularly the mitochondria,as well as the importance of pharmacologi-cal treatments that target the mitochondriasuch as taking ubiquinone (coenzyme Q10[CoQ10]). An in-depth understanding andrecognition of the importance of mitochon-dria will assist clinicians in understanding,preventing, and treating diseases often ob-served in the emergency department (ED).
Table 1. Description of selected organelles of the cell
Actin: A protein located in the microtubule, involved in contraction of the muscle and cell division,
motility, and signaling.
Cytosol: The fluid component of cytoplasm in which all organelles are located.
Endoplasmic reticulum: Tubular network of membranes that is responsible for transportation of
chemicals throughout the cell.
Golgi complex (apparatus): Stacks of membrane-bound vesicles and vacuoles that lie adjacent to
the nucleus that package molecules for transport.
Lysosome: Small and round organelles that are responsible for digestion of cell waste.
Mitochondria: Membrane-bounded organelles that are responsible for adenosine triphosphate
synthesis essential to metabolism of the body.
Nucleolus: Spherical in shape, produces and assembles ribosome components.
Nucleus: Large, oval-shaped organelle that contains deoxyribonucleic acid. It is responsible for
processing cell information and controls cell activities such as growth and protein synthesis.
Peroxisome: An organelle that contains enzymes that are responsible for molecule import and
removal of toxins within the cell.
Plasma membrane: A selectively permeable outer layer made of proteins, provides transportation of
ions and protection to the cell.
Tubulin (α-tubulin and β -tubulin): Globular proteins that make up the microtubules that assist in
cell support.
Note. From “Effect of NaC1 and KC1 on Phosphatidylcholine and Phosphatidylethanolamine Lipid Membranes: Insight
from Atomic-Scale Simulations for Understanding Salt-Induced Effects in the Plasma Membrane,”by A. Gurtovenko, and
I. Vattulainen, 2008, The Journal of Physical Chemistry B, 112(7), 1953–1962; and “Mitochondrial Diseases in Man
and Mouse,”by D. C. Wallace, 1999. Science, 283(5407), 1482–1488. Reprinted with permission of authors.
CELL STRUCTURE AND FUNCTION
Billions of cells that vary in size and shapemake specialized tissues and organs possi-ble. Many drugs target specific cell structures,making the significance of organelle knowl-edge great to those administering medica-tions. Most cells are surrounded by a plasmamembrane and contain a nucleus and multi-ple organelles. Table 1 is a review of the struc-ture and function of some selected organellesin a cell. Organelles within the cell are sur-rounded by membranes that allow for segre-gation and communication. Figure 1 is an il-lustration of the different organelles withinthe cell. Each organelle has a function thataccounts for the cell’s viability; however, themitochondrion is a small organelle with im-mense responsibilities including generationof cellular energy and respiration (Wallace,1999).
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Figure 1. The cell and some of the organelles in a three-dimensional view. Reproduced with permission
from Invitrogen, Carlsbad, CA.
Structurally, the mitochondria are thread-shaped organelles that are compartmental-ized, with an outer membrane surroundingan inner membrane folded into fingerlike ob-jects called cristae (Murphy & Smith, 2000).Cristae have layers called lamellae that in-crease surface area and reduce transport time(Mannella, 2006; Paumard et al., 2002). Theporous outer membrane is made of pro-tein structures and is permeable to smallermolecules because of its phospholipid bilayer.The convoluted inner membrane containsenzymes and metabolic pathways that assistin adenosine triphosphate (ATP) production.The outer and inner membranes generatethe intermembrane space that containsmany proteins that are essential in metabolicpathways. The viscous matrix space of themitochondria contains ribosomes, enzymes,and proteins that are necessary for differentmetabolic pathways such as the citric acidcycle (Murphy & Smith, 2000). Figure 2illustrates a mitochondron with the outer andinner membranes, cristae, and matrix space.The mitochondria function as the hemi ofthe cell, much of the oxygen taken in duringrespiration is used by the mitochondria toproduce energy needed by the cell (Murphy& Smith, 2000). Hemi is an abbreviation
for an engine whose combustion chamberis hemispherical to produce a more evenburning of fuel, which makes the enginemore powerful. Thus, the hemi of the cellrefers to the mitochondria, which are theenergy-producing structure of cells.
Figure 2. The mitochondria: inner and outer
membranes, the cristae, and the matrix space.
From Pathophysiology: Concepts of Altered HealthStates (6th ed., p. 68), by C. M. Porth, 2002,
Philadelphia: Lippincott Williams & Wilkins. Copy-
right 2002 by Lippincott Williams & Wilkins. Re-
produced with permission.
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During the normal metabolism of oxygenin the mitochondria, ROS are produced asbyproducts. ROS are a reduction–oxidationderivative of molecular oxygen and are highlyreactive molecules that play an importantrole in cell signaling (Murrant & Reid, 2001).ROS are highly reactive because they haveunpaired electrons in the valence shell.Examples of ROS include superoxide, hydro-gen peroxide, and hydroxyl radicals. ROSplay a role in cytotoxicity through alter-ations in protein, lipid, and nucleic acid struc-ture and function (Tarpey, Wink, & Grisham,2004). Alterations occur by a posttranslationalreduction–oxidation modification based onthe level of ROS exposure in proteinsand oxidization in lipids and nucleic acids(Forrester & Stamler, 2007). ROS levels in-crease during times of stress, and the resultmay be damage to the mitochondria’s struc-ture and function.
Cytochrome C
When a person is under stress, many sub-stances are released including a proteincalled p66Shc. This protein takes electronsfrom the mitochondrial cytochrome c anduses them to produce hydrogen peroxide(Orsini et al., 2006). If ROS production istoo great, mitochondria lose the ability tosynthesize ATP, and this leads to dysfunctionof the sodium–potassium pump on the cellmembrane. This results in cell swellingand the release cytochrome c, which leadsto activation of caspases and induction ofapoptosis (Wakabayashi, 2002). Cytochromec, a component of the mitochondrial electrontransport chain, initiates caspase activationwhen released from the mitochondria (Liu,Kim, Yang, Jemmerson, & Wang, 1996;Wang, 2001). Caspases are proteins thatcan affect cytosolic and nuclear substratesresulting in apoptosis (Green & Reed, 1998).Cytochrome c, even without the overpro-duction of ROS, is released to cause celldeath in response to deoxyribonucleic acid
(DNA) damage or infection (Skulachev,1998).
Apoptosis
Apoptosis is a programmed cell death thatnaturally occurs in the body to maintainhomeostasis. Multiple apoptotic pathways arestimulated by mitochondrial activity (Wang,2001). When there are disruptions in thispathway, apoptosis may occur more or lessfrequently than normal, causing pathologicproblems (Murphy & Smith, 2000). Duringcertain phases of apoptosis, uncoupling ofthe mitochondria occurs and is followed byDNA degradation (Kroemer, Petit, Zamzami,Vayssiere, & Mignotte, 1995). In addition,metabolic changes may occur within the mi-tochondria during apoptosis, resulting in en-zymatic reactions that directly impact mito-chondrial function (Wang, 2001). As a result,cellular defects occur that may lead to variousdisease states (Wallace, 1999).
Mitochondrial DNA Mutation
Mitochondrial DNA (mtDNA) mutation can bethe cause for many diseases as well (Clayton,1991). The mtDNA is circular, small, andsimple compared with nucleic DNA (Murphy& Smith, 2000; Wallace, 1999). An interestingdetail about mtDNA mutation and disease isthat with more mutated nuclei, more severeclinical symptoms will be seen (Lightowlers,Chinnery, Turnbull, & Howell, 1997). ATPproduction can be decreased with mtDNAmutation; therefore, cells that depend onmitochondrially generated ATP are at thegreatest risk for disease (DiMauro & Schon,2001). Many patients who are admitted to theED have clinical conditions from mitochon-drial dysfunction caused by ROS and mtDNAdamage (Murphy & Smith, 2000; Pieczenik &Neustadt, 2007; Tarpey et al., 2004).
Other Substances That Accelerate
Mitochondrial Damage
There are other substances that have beendemonstrated to accelerate some mitochon-drial disorders. The two most common are
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alcohol and cigarette smoke. Alcohol pro-motes calcium activation of the mitochondrialpermeability pore, resulting in cytochrome crelease and subsequent apoptosis (Hajnoczky,Buzas, Pacher, Hoek, & Rubin, 2005). Withcigarette smoke, the carbon monoxide de-stroys the mitochondria by inhibiting Com-plex IV of mitochondrial oxidative phospho-rylation (Gvozdjakova et al., 1984; Leone, Lan-dini, Biadi, & Balbarini, 2008).
Surprisingly, a treatment frequently usedin the ED has been shown to cause mito-chondrial damage—too much oxygen. Whencells are exposed to hyperoxia, there is anabundance of free radicals, which can induceextensive mitochondrial damage (Pagano,Donati, Metrailler, & Barazzone Argiroffo,2004; Scatena et al., 2004). Of course, too lit-tle oxygen, hypoxia, also results in anaerobicmetabolism and decreased ATP productionby the mitochondria.
CLINICAL SIGNIFICANCE
One of the first articles about mitochondrialmedicine in emergency medicine was aboutthe role of mitochondria and emphasizedthe importance of emergency medicine per-sonnel understanding mitochondrial dysfunc-tion and treatment therapies (Watts & Kline,2003). All of the major organs of the body re-quire a substantial amount of energy to per-form their functions, so it is not surprisingthat serious illness can be the result or thecause of mitochondrial dysfunction (Murphy& Smith, 2000).
Disease Processes That Cause
Mitochondrial Dysfunction
As adults age, they may develop severedefects of mitochondrial function, leadingto different disease states. These includecancer, Type 2 diabetes, atheroscleroticheart disease, transient ischemic attacks,Alzheimer’s disease, and Parkinson’s disease.Furthermore, mitochondria can be damagedby medications such as simvastatin, haloperi-dol, and captopril (Casademont et al., 2007;
Gvozdjakova et al., 1999; Schick et al., 2007).While mitochondrial-specific diseases arenow being discovered, it still remains achallenge to confirm diagnoses due to mi-tochondrial DNA mutations because of thecomplexities of the genotype–phenotypecorrelations (Wong, 2007). When there isdamage to the mitochondria, organs will beaffected and disease will occur. Certain phar-macological treatments are used to target themitochondria because of their role in energymetabolism, ROS production, and apoptosis.For example, atenolol and carvedilol havebeen shown to have antioxidant effects andinhibit mitochondrial cytochrome c release,which may reduce overall mortality anddecrease heart failure-related cell damage(Lechat et al., 1998; Packer et al., 1996;Romeo, Li, Shi, & Mehta, 2000). Thus, whenthese drugs are ordered, personnel adminis-tering these treatments need to understandon a cellular level what might be occurring. Acommon example of a disease that is observedby healthcare professionals in the ED is MI.
Research has indicated that during my-ocardial injury the mitochondrial structureand function are abnormal (Marin-Garcia &Goldenthal, 2002; Zang, Maass, White, &Horton, 2007). During the ischemic process,mitochondrial ROS production increases andoxidative stress occurs (Shohet & Garcia,2007; Zorov, Filburn, Klotz, Zweier, & Sollott,2000). An MI is preceded by increased ROSand decreased ATP production within themitochondria, leading to apoptosis (Websteret al., 2006). To decrease the amount ofROS produced during an MI, antioxidanttherapy targeting the mitochondria could bebeneficial in preventing an overabundanceof oxidative stress and further damage. Cur-rently, there are many therapies being testedin humans to reduce myocardial injury suchas antioxidants, caspase inhibitors, insulin-like growth factor-1, and calcium-channelblockers (Khoynezhad, Jalali, & Tortolani,2004; Ratnam, Ankola, Bhardwaj, Sahana, &Kumar, 2006).
Another condition commonly treated in theED is burns. In any burn, oxidative stress
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occurs; however, in a severe burn it couldbe the major factor contributing to organ fail-ure (Horton, 2003). Studies have shown thatto decrease burn-related immunosuppressionand improve the function of the organs aftera burn, antioxidant therapy should be used(Cetinkale, Senel, & Bulan, 1999; Tauskela,2007). A study on the beneficial effects of an-tioxidant therapy found that antioxidant vi-tamin therapy prevented cardiac dysfunctionby preventing the loss of mitochondrial mem-brane integrity related to the burn (Zang et al.,2007).
Diabetes is another disease associated withmitochondrial dysfunction (Nisoli, Cozzi,& Carruba, 2008; Schrauwen & Hesselink,2004). Type 2 diabetes is associated withmitochondrial dysfunction, suggesting thatprevention and treatment should focuson the mitochondrial targets (Wiederkehr &Wollheim, 2006). Mitochondrial ROS increasein response to hyperglycemia, which canlead to complications such as renal disease(Forbes, Coughlan, & Cooper, 2008). Inskeletal muscle, patients with diabetes have alower mitochondria population, which helpsto explain the decrease in rates of oxidativephosphorylation (Civitarese & Ravussin,2008). Investigators have found that lifestylechanges can increase the number of mito-chondria and help control diabetes (Toledoet al., 2007, 2008).
Diseases Resulting From Mitochondrial
Mutation
There are many specific mitochondrial dis-eases, such as diabetes mellitus, Hunting-ton’s chorea, and primary biliary sclerosis, toname a few. The United Mitochondrial Dis-ease Foundation (UMDF) was started to sup-port all sufferers of mitochondrial disorders.The Foundation’s Web site lists over 50 mito-chondrial diseases and describes how thesediseases are related to mitochondrial defectsor injury (UMDF, n.d.). These mitochondrialdiseases directly affect the mitochondria andare caused by DNA mutation. However, theproduction of ROS inside the mitochondria as
well as frequent DNA mutations links the mi-tochondria to multiple diseases and cancers(Klaunig & Kamendulis, 2004).
Thermal regulation may not be normal inpatients with mitochondrial diseases, and ex-posure to cold can result in severe heat loss(Farhadi et al., 2005; Tanaka, Takeyasu, Fuku,Li-Jun, & Kurata, 2004). Conversely, exposureto heat can lead to heat exhaustion and heatstroke because some patients with mitochon-drial diseases cannot sweat normally (Clay,Behnia, & Brown, 2001).
Therapies
Ubiquinone, also called CoQ10, is used as adietary supplement and acts as an antioxi-dant by reducing ROS production and thusmitochondrial damage (Crane, 2001; Dallner& Sindelar, 2000). Ubiquinone is present inmost human cells and is responsible for theproduction of ATP. With the assistance ofubiquinone, glucose is converted to ATP inthe mitochondria. Ninety-five percent of ATPis converted with the help of ubiquinone(Ernster & Dallner, 1995). Therefore, or-gans with the highest energy requirementswill have the highest ubiquinone concentra-tions (Aberg, Appelkvist, Dallner, & Ernster,1992; Okamoto, Matsuya, Fukunaga, Kishi,& Yamagami, 1989; Shindo, Witt, Han, Ep-stein, & Packer, 1994). In the clinical set-ting, ubiquinone is now being used to treatmetabolic disorders, as well as serious mito-chondrial diseases (Berbel-Garcia et al., 2004).Ubiquinone has been found to have beneficialeffects on patients who suffer from migraineheadaches, MI, and cancer (Rozen et al.,2002; Sandor et al., 2005). For those withlow levels of ubiquinone, this substance of-fers a prophylactic effect that provides the mi-tochondria with the ability to create enoughATP (Haas, 2007; Littarru & Tiano, 2007).
Mitoquinone mesylate (MitoQ®) is an an-tioxidant that can target mitochondrial dys-function. When delivered to the intracellu-lar region where increased levels of ROSare present, mitoquinone mesylate func-tions similar to ubiquinone (Tauskela, 2007).
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Mitoquinone mesylate has been accepted bythe United States Food and Drug Administra-tion for use in clinical trials; future approvalis anticipated and may lead to use in EDs. InPhase II clinical trials in patients with liver dis-eases, mitoquinone mesylate (40–80 mg PO)was administered once a day with no reportedadverse effects (Tauskela, 2007).
Other antioxidants scavenge free radicalsand help prevent mitochondrial damage.These include vitamin C, vitamin E, lycopene,and α-lipoic acid (McMackin et al., 2007;Ratnam et al., 2006). For example, vitaminC has been shown to reduce mitochondrialdamage in congestive heart failure (Rossiget al., 2001). Administering vitamin E to pa-tients with Type 2 diabetes decreases mito-chondrial damage (Faure, 2003).
CONCLUSION
Many patients admitted to the hospital arefirst assessed in the ED. To effectively pre-vent further cellular damage and treat thesepatients, an understanding of cell biology isnecessary to comprehend the therapeutic ef-fects of clinical treatment. Injured patientswill have an abundance of ROS production, re-sulting in damage to the mitochondria’s struc-ture and function. When this damage occurs,cytochrome c is released, resulting in the ini-tiation of apoptotic caspases that ends in celldeath and disease. ED clinicians should recog-nize the importance of maintaining mitochon-drial function as part of preventative care andoptimizing the patient’s health. This allowsthe mitochondria to produce ATP and fulfillits duty as the hemi of the cell.
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Aberg, F., Appelkvist, E. L., Dallner, G., & Ernster, L.
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Anderson, K. M., Seed, T., Ou, D., & Harris, J. E. (1999).
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grammed cell death. Medical Hypotheses, 52(5),
451–463.
Berbel-Garcia, A., Barbera-Farre, J. R., Etessam, J. P., Salio,
A. M., Cabello, A., Gutierrez-Rivas, E., et al. (2004).
