Ⅵ REVIEW ARTICLE David C. Warltier, M.D., Ph.D., Editor Anesthesiology 2006; 105:819–37 Copyright © 2006, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Clinical Implications of Mitochondrial Dysfunction Stanley Muravchick, M.D., Ph.D.,* Richard J. Levy, M.D.† Mitochondria produce metabolic energy, serve as biosensors phosphorylation,1 a process conducted by a series of five for oxidative stress, and eventually become effector organelles enzyme complexes located on the inner mitochondrial Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/105/4/819/360218/0000542-200610000-00029.pdf by guest on 25 September 2021 for cell death through apoptosis. The extent to which these membrane (fig. 1). Four of these complexes comprise manifold mitochondrial functions are altered by previously unrecognized actions of anesthetic agents seems to explain and the mitochondrial electron transport chain (ETC) and link a wide variety of perioperative phenomena that are cur- function as a biochemical “conveyor belt” for electrons. rently of interest to anesthesiologists from both a clinical and a Oxidative phosphorylation couples the oxidation of re- scientific perspective. In addition, many surgical patients may duced nicotinamide adenine dinucleotide and flavin ad- be at increased perioperative risk because of inherited or ac- enine dinucleotide, generated by the Krebs cycle and by quired mitochondrial dysfunction leading to increased oxida- ␤ tive stress. This review summarizes the essential aspects of the the -oxidation of fatty acids, to the phosphorylation of bioenergetic process, presents current knowledge regarding adenosine diphosphate (ADP) to adenosine triphosphate the effects of anesthetics on mitochondrial function and the (ATP). Electron donation to complex I (reduced nicotin- extent to which mitochondrial state determines anesthetic re- amide adenine dinucleotide–ubiquinone oxidoreduc- quirement and potential anesthetic toxicity, and considers some of the many implications that our knowledge of mito- tase) initiates this process. Alternatively, electrons orig- chondrial dysfunction poses for anesthetic management and inating from succinate and from reduced flavin adenine perioperative medicine. dinucleotide can be channeled into the ETC through complex II (succinate–ubiquinone oxidoreductase). MITOCHONDRIA not only generate and modulate bioen- Electrons are transported from complex I or II to com- ergy but also serve as the final effectors for the termina- plex III (ubiquinone–cytochrome c oxidoreductase) via tion of cell viability as organisms approach the end of a mobile electron carrier, coenzyme Q (ubiquinone), their lifespan. Therefore, the implications of these pro- and subsequently on to complex IV (cytochrome c oxi- cesses with regard to understanding evolution, disease, dase) via cytochrome c. Complex IV uses electrons from aging, and death are profound. Particularly relevant to cytochrome c to reduce molecular oxygen, the final anesthesiologists is the role of mitochondria in determin- acceptor of electrons, to water at that site. ing the response of the nervous system to anesthetic Intrinsically linked to this process of electron transport agents, in initiating mechanisms of cell injury or protec- is the generation and maintenance of a hydrogen ion tion after ischemic, hypoxic, or toxic injuries, and their gradient across the inner mitochondrial membrane. The ability to precipitate critical illness in individuals with inner membrane separates the intermembrane space inherited or acquired mitochondrial disorders. These from the mitochondrial matrix. The gradient is estab- aspects of mitochondrial biology and pathophysiology lished by proton pumps in ETC complexes I, III, and IV. will be briefly summarized in this clinically oriented The F1F0–ATPase (ATP synthase) complex within the review. inner membrane uses this proton motive force to phos- phorylate ADP. This last step in the overall process of The Bioenergetic Process oxidative phosphorylation produces the ATP that serves as the fundamental “currency” needed for most energy- Mitochondria produce the energy needed for normal requiring biologic transactions. Another membrane-inte- cellular function and metabolic homeostasis by oxidative grated protein, adenine nucleotide translocase, regulates an “antiport” process that moves ADP and ATP in oppo- * Professor of Anesthesiology and Critical Care, Hospital of the University of site directions across the inner mitochondrial mem- Pennsylvania. † Assistant Professor of Anesthesiology and Pediatrics, Depart- ment of Anesthesiology and Critical Care Medicine, Division of Cardiothoracic brane. Adenine nucleotide translocase delivers ATP to Anesthesiology, The Children’s Hospital of Philadelphia. energy-requiring sites, mostly in the cytosol, and simul- Received from the Department of Anesthesiology and Critical Care, University taneously resupplies the ATP synthase complex with of Pennsylvania School of Medicine, and the Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania. Submitted for publication July 15, 2005. Accepted for new substrate. publication June 20, 2006. Support was provided solely from institutional and/or The hydrogen ion gradient established by the process departmental sources. Address correspondence to Dr. Muravchick: Department of Anesthesiology and of oxidative phosphorylation can also be dissipated by Critical Care, Dulles Suite 680, Hospital of the University of Pennsylvania, 3400 proton leakage back into the matrix through the inner Spruce Street, Philadelphia, Pennsylvania 19104-4283. [email protected]. Individual article reprints may be purchased through the Journal Web site, www. membrane that bypasses the ATP synthase complex. anesthesiology.org. Uncoupling proteins (UCPs) within the inner membrane Anesthesiology, V 105, No 4, Oct 2006 819 820 S. MURAVCHICK AND R. J. LEVY Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/105/4/819/360218/0000542-200610000-00029.pdf by guest on 25 September 2021 Fig. 1. Schematic representation of the mitochondrial components needed for oxidative phosphorylation. Complexes I–IV, located within the inner mitochondrial membrane, are oxidase complexes that, along with coenzyme Q (Co Q) and cytochrome c (Cyto C), comprise the electron transport chain. Dotted lines indicate pathway for electron flow. Complexes I, III, and IV also pump hydrogen ions (dashed lines) into the intermembrane space and generate the electrochemical gradient that ultimately powers the phosphor- ylation of adenosine diphosphate (ADP) to adenosine triphosphate (ATP) by ATP synthase. Inner membrane–bound uncoupling protein (UCP) is an alternate return path for hydrogen ions. Adenine nucleotide translocase (ANT) regulates the balance of ATP and ؍ ؍ ؍ ADP within the mitochondrial matrix. FADH2 flavin adenine dinucleotide; H2O water; NAD nicotinamide adenine dinucle- ؍ ؍ ؍ otide; NADH reduced nicotinamide adenine dinucleotide; O2 oxygen; Pi inorganic phosphate. Copyright © 2000 American Diabetes Association. Modified with permission from The American Diabetes Association, from Boss et al.4 provide this alternate pathway for proton influx. In ef- subunits needed for electron transport and oxidative fect, UCPs convert some of the electrochemical energy phosphorylation, although the majority of mitochondrial generated by the ETC into heat rather than into ATP. The proteins needed for normal bioenergetic function are rate of proton leakage through a UCP seems to be influ- encoded by nuclear DNA (nDNA)7 and therefore must enced by a variety of conditions, including changes in be imported into the mitochondrial matrix from the cell the magnitude of the hydrogen ion gradient itself, in- cytosol.8 Complex IV of the ETC, for example, contains creased catecholamines levels, and variations in fatty 13 subunits, 10 of which are encoded in nDNA. The acid concentrations.2 UCP-1, also called thermogenin, expression of the mitochondrial genome itself requires a was originally characterized in the mitochondria of single mitochondrial transcription factor that arises from brown fat cells3 and is now known to play a role in the nuclear genome.9 nonshivering thermogenesis in human neonates. Subse- Overall, the human mitochondrial genome encodes for quently, additional UCP isoforms were identified in a 13 peptides (subunits of complexes I, III, and IV and the 4 variety of tissues. Although their precise metabolic ATP synthase complex), 2 ribosomal ribonucleic acids functions have yet to be determined, UCPs may play an (RNAs), and 22 transfer RNAs. Nuclear DNA encodes for 5 important role in adult obesity, diabetes mellitus, and at least 1,000 proteins that are needed for mitochondrial perhaps other conditions where the regulation of oxida- bioenergetic and metabolic functions and for mtDNA tive metabolism seems to be disrupted. expression and replication.10 Although there may be as many as 1,000 copies of mtDNA in most cells, acquired mtDNA point mutations and base pair deletions are ex- Mitochondrial Biogenesis tremely rare and are normally found in only a minute proportion of total mtDNA11 despite the fact that The mitochondrion, unique among mammalian or- mtDNA, unlike nDNA, lacks histone protection and is ganelles, contains multiple copies of a small circular surrounded by potentially damaging oxidative influenc- genome of approximately 16,000 nucleotide base pairs. es.12 This observation supports the hypothesis that there This mitochondrial DNA (mtDNA)