Quick viewing(Text Mode)

Review the Development of Mitochondrial Medicine

Review the Development of Mitochondrial Medicine

Proc. NatI. Acad. Sci. USA Vol. 91, pp. 8731-8738, September 1994 Review The development of mitochondrial medicine Rolf Luft The Roff Luft Research Institute, Department of Molecular Medicine, Karolinska Hospital, S-171 76 Stockholm, Sweden

ABSTRACT Primary defects in mito- provide a short review concentrating on ylation. These features of "loosely cou- chondrial function are implicated in over those aspects most relevant to clinical pled" respiration-deficient respiratory 100 diseses, and the list continues to grow. medicine. In the accompanying review control with a partially maintained ability Yet the first mitochondrial defect-a myo- (174), Wallace describes the molecular, to synthesize ATP-accounted for the pathy-was demonstrated only 35 years biological, and evolutionary implications symptoms of the patient: abnormal pro- ago. Thefield's dramatic expansion reflects of mitochondrial . duction of heat, which the body tried to growth of knowledge in three areas: (i) relieve by increased perspiration, and characterization of mitochondrial struc- The Birth of Mitochondrial Medicine enormous caloric intake to compensate ture and function, (i) euiation of the (1959-1962): Luft for the increased combustion. steps involved in mitochondrial biosynthe- The mitochondria in this patient were sis, and (Ni) discovery ofspecific mitochon- The first patient found to have a mito- also insensitive to oligomycin, a drug drial DNA. Many mitochondrial diseases chondrial disease was a 30-year-old which interferes with the tight coupling of are accompanied by in this DNA. woman who developed clinical symptoms electron transport to phosphorylation Inheritance is by maternal t ission. at the age of 7. Her dominant symptoms without inhibiting ATP synthesis. A ten- The metabolic defects encompass the elec- were enormous perspiration combined tative explanation for this observation tron transport complexes, intermediates of with markedly increased fluid intake but was an " leak" above the level of the tricarboxylic acid cycle, and substrate without polyuria; extremely high caloric the phosphorylating system. Such a pro- transport. The clinical manifestations are intake (above 3000 kcal perday) at a stable posal was supported by the observation in protean, most often involving skeletal mus- body weight of 38 kg and a body height of the second patient with this disease, Luft cie and the central nervous system. In 159 cm; and general weakness, particu- disease (2-4), of an energy-dissipating fu- addition to being a primary cause of dis- larly prominent in her musculature. The tile cycle of Ca2+ uptake and release- ease, mitochondrial DNA mutations and dominating laboratory finding was a basal i.e., a waste ofenergy without a change in impaired oxidation have now been found to metabolic rate (BMR, a measure of oxy- calcium concentration. Other remarkable occur as secondary phenomena in aging as gen consumption) of + 180%. Thyroid findings in the first patient's mitochondria weli as in age-related degenerative diseases function was normal. Subtotal thyroidec- were a high level of cytochrome oxidase, such as Parkinson, Alzheimer, and Hun- tomy with administration of thyroid- a relatively low level of coenzyme Q, and tington diseases, amyotrophic lateral scle- depressing drugs was followed by classi- a high content of RNA in a muscle ho- rosis and cardiomyopathies, atherosclero- cal myxedema but with a BMR of +100%o. mogenate, one piece of evidence for in- sis, and meflitus. Manifestations of Following the idea that the patient's creased mitochondrial synthesis. both the primary and secondary mitochon- enormously elevated BMR must involve Electron microscopy (Fig. 3) of the drial diseases are thought to result from the mechanisms regulating oxygen consump- mitochondria revealed striking structural production of oxygen free radicals. With tion at the cellular level, studies were un- abnormalities: large accumulations ofmi- increased understanding of the mecha- dertaken that focused on the mitochondria tochondria of highly variable size in the nisms underlying the mitochondrial dys- of . By 1960, studies on rat perinuclear zone of the muscle cells and functions has come the beginnings of ther- liver mitochondria had already shown that vast paracrystalline inclusions, possibly apeutic sttegies, based mostly on the ad- this is site of respiration and composed of lipofuscin granules. ministration of antioxidants, replacement respiration-regulated phosphorylation. Several explanations for the loose cou- of cofactors, and provision of nutrients. At Uptake of oxygen by mitochondria was pling were tested, using techniques then the present accelerating pace of develop- known to be controlled by the components available. These studies suggested that a ment of what may be cafled mitochondrial of ATP production (inorganic phosphate, short circuit of the flow of protons in the medicine, much more is likely to be Pi, and the phosphate acceptor, ADP). inner membranes had occurred, partly achieved within the next few years. This respiratory control allows the body to inhibiting ATP production-but preserv- adapt oxygen consumption to actual en- ing electron transport. No uncoupling In 1959, the first biochemical studies of a ergy need. The patient's condition, a pri- agent--e.g., thermogenin (5)-was found cell organelle in humans were undertaken, ori, could then be ascribed to a derange- in muscle homogenates. following observations made atthe bedside ment of respiratory control. Another assumption was that the lack of of a patient with striking symptoms, never Biochemical studies of isolated skele- respiratory control might be due to en- before encountered. These clinical obser- tal muscle mitochondria from the patient vations, first, led to an idea about the origin 1 and (Figs. 2) demonstrated a nearly Abbreviations: KSS, Kearns-Sayre syndrome; ofthe symptoms and, second, to studies of maximal rate of respiration in the pres- MERRF, and ragged red the particular organelle: the ence of substrate alone without addition fibers (syndrome); LHON, Leber hereditary (1). The pathophysiology ofthe mitochon- of ADP + Pi, but an almost normal phos- optic neuropathy; MELAS, mitochondrial my- dria developed gradually over the years as phorylating efficiency (expressed as the opathy, , , and relevant discoveries were made in bio- P/O ratio) in the presence ofADP and Pi. -like episodes; CPEO, chronic progres- cell and sive external ophthalmoplegia; CNS, central chemistry, biology, molecular bi- The mitochondria also exhibited high nervous system; LDL, low density lipoprotein; ology. During the past few years the field ATPase activity, which was only slightly NIDDM, non-insulin-dependent diabetes mel- mitochondrial medicine has expanded stimulated by 2,4-dinitrophenol, a known litus; IDDM, insulin-dependent diabetes melli- dramatically, in several directions. I here uncoupler of respiration from phosphor- tus; MHC, major histocompatibility complex. 8731 Downloaded by guest on September 23, 2021 8732 Review: Luft Proc. Natl. Acad. Sci. USA 91 (1994) A B C D . - 1 --a I E 0.4 it i i . _ C+i> D __ - 0 X~~i °-- 0 ° 0.2- i. E5 E 0.1- 9 IN - ftI E 73- o I 1- ! 2 -lmin4- U, 0o

FIG. 1. Effect of Pi, ADP, and oligomycin on respiration of skeletal muscle mitochondria from a normal subject (A and B) and from the hypermetabolic patient (C and D). hanced proliferation ofmitochondria, with review of the biochemical basis of mito- (MELAS), with episodic vomiting, lactic the formation of a component necessary chondrial diseases classified more than acidosis, and myopathy with ragged red for maintaining tight coupling between res- 120 entities (13). All were based on alter- fibers, sometimes , generalized piration and phosphorylation having failed ations in mitochondrial biochemistry. , deafness, and short stature; (v) to keep pace with the proliferation (6). From Scholte's and subsequent re- Leigh disease or subacute necrotizing en- Coenzyme Q might be a candidate for views several basic principles in mito- cephalomyopathy, with respiratory abnor- this-in the first patient its level was de- chondrial pathology emerged. First, malities, weak cry, impaired feeding, im- creased relative to cytochrome oxidase. some mitochondrial diseases affect only paired vision and hearing, ataxia, weak- The biochemical and morphological one tissue, most often skeletal muscle ness, and hypotension; (vi) chronic findings in Luft disease would have an and brain but also liver, heart, kidneys, progressive external ophthalmoplegia impact on the further development of or endocrine glands. Other organs may (CPEO) and , mitochondrial pathophysiology with the be involved secondarily. The disease with symptoms similar to those in KSS but growth of the field in the 1970s. may originate as a specific defect in mi- also ocular myopathy, retinitis pigmen- tochondrial function, but a variety of tosa, and central nervous system (CNS) Growth of the Field of Mitochondrial genetic and environmental factors may dysfunction; and (vii) Alper syndrome or Disease contribute to the phenotype. progressive infantile poliodystrophy, with Despite the diversity ofclinical phenom- seizures, dementia, spasticity, blindness, At the beginning of the 1970s it was ena and mitochondrial pathology, seven and liver dysfunction accompanied by spe- realized that aberrations of the respira- syndromes have been particularly impor- cific cerebral degeneration. tory chain with or without structurally tant in advancing our understanding of The clinical expressions of these and abnormal mitochondria of the type ob- mitochondrial medicine: (i) Kearns-Sayre other mitochondrial syndromes may vary served in Luft disease also occurred in syndrome (KSS), with ophthalmoplegia, considerably. Overlapping between the certain other myopathies not associated retinal pigmental degeneration, sometimes syndromes is common and may make with elevated oxygen consumption (7). In heart block, ataxia, hyperparathyroidism, diagnosis difficult. Clearly, tissues with a 1970-1972, respiratory chain deficiencies and short stature; (ii) myoclonus epilepsy high demand for ATP and oxidative turn- in disorders mainly involving central ner- and ragged red fibers syndrome over are preferentially affected in differ- vous system (CNS) and skeletal muscles (MERRE), with intense myoclonus, epi- ent combinations. In some syndromes, were reported (8-10). In the following lepsy, progressive ataxia, muscle weak- endocrine glands are involved with signs year, the first examples were reported of ness and wasting, deafness, and dementia; ofdiabetes, hypoparathyroidism, stunted myopathies due to isolated deficiencies (iii) Leber hereditary optic neuropathy growth, etc. Inherited factors are present of muscle carnitine (11) and carnitine (LHON), with blindness in men, at times in some, if not all, of these syndromes. palmitoyltransferase (12). movement disorders and encephalomyop- Maternal inheritance is well established These additional clinical discoveries athy, electrocardiogram abnormalities, in MERRF and LHON. were the starting point for rapid expansion and retinal microangiopathy; (iv) mito- A common feature in this group of in the field of mitochondrial pathophysi- chondrial myopathy, encephalopathy, lac- inborn metabolic errors is the involve- ology. By 1988, Scholte's comprehensive tic acidosis, and stroke-like episodes ment of specific enzymes in the pathway of aerobic energy production in the mi- Respiration ATPase activity Respiration ATPase activity tochondria. Thus, there is a defect in coenzyme Q metabolism in KSS; re- duced activities ofrespiratory complexes 6 6 CL Q. CLZz 1 5 15E I and IV in MERRF; reduced activity in 0 z CL 0 0 + 5 + 04 complex I in LHON; reduced activities in : + Racceptor P-acceptor / E (P/O=2.9) 1 2 (P/O= 2.6) complex I and in 4 - 2co 0 MELAS; and reduced activity in cy- o/En 9a tochrome c oxidase in . 3-3 3 .. 4-3 l.9 ., :1I" 0 6 IIa 6pu The Discovery of Specific Mitochondrial 0 2- 2 d6 * -P-acceptor EL DNA (1963-1964) and of Mutations 1/ . i 3 ° in It (1988) >->,RaccePt9L

5 10 15 20 25 5 10 15 20 25 That DNA is present in mitochondria Time, min Time, min (mtDNA) was first clearly shown in 1963 by Nass and Nass (14) in chick embryos FIG. 2. Respiratory control, phosphorylation efficiency, and ATPase activity of isolated and by Schatz et al. (15), who isolated skeletal muscle mitochondria from a normal subject (Left) and from the hypermetabolic patient DNA from purified yeast mitochondria. (Right). DNP, 2,4-dinitrophenol. By 1981 the complete sequence of human Downloaded by guest on September 23, 2021 ReUview: Luft Proc. Natl. Acad. Sci. USA 91 (1994) 8733 radic human encephalomyopathies with its gene products. AIDS patients under- large deletions of mtDNA (24) and a going long-term treatment with azidothy- G-to-A transition at nucleotide midine (AZT) developed destructive mi- pair 11778 in the mtDNA ofpatients with tochondrial myopathy with ragged red LHON (25). A constant feature in LHON fibers and markedly reduced amounts of has been the coexistence of mutant and mtDNA in skeletal muscle, and this de- wild-type mtDNA (). Fol- pletion was reverted in one patient after lowing these reports, other clinical syn- withdrawal of AZT (43). dromes were soon linked to specific mu- tations, deletions, and duplications of Free Radicals, Oxidative Damage, mtDNA, impairing protein synthesis of and Antioxidants the mitochondrial subunits of the respi- ratory chain complexes-e.g., point mu- Essential for the discussion of mitochon- tations of the tRNALYS gene in the drial pathophysiology is abriefsummary of MERRF syndrome (26) and a point mu- oxidative processes in mitochondria and tation of the tRNAb'R gene in MELAS the consequences ofabnormalities in those (27). Most of the "classical" mitochon- processes. Molecular oxygen has the abil- drial disorders have since been submitted ity to take up electrons (e-) from the sur- to detailed studies (for reviews, see refs. roundings, and these electrons are easily 28-31). A special feature of these tRNA exchangeable. During normal aerobic res- mutations is that they have indistinguish- piration, mitochondriaconsume 02, reduc- able consequences at the biochemical FIG. 3. Electron micrograph from a mus- ing it stepwise to form H20 (Fig. 4). level, producing partial defects in the During this process, four electrons are cle fiber of the hypermetabolic patient. Cell mtDNA-dependent respiratory com- nucleus (n) and a multitude of mitochondria added, and energy released is conserved (m) surrounding it. On the right is a bundle of plexes. In sporadic adult-onset CPEO as ATP. The chemical oxidants, *O2 and dense cell incusions. (x4700.) with ragged red fibers, large-scale dele- -OH, are normal products of the oxida- tions ranging from 1.3 to 7.6 kb (32-35) or tive process. Entities with such unpaired mtDNA was elucidated (16). Unlike nu- duplications (36) were observed in about electrons and with reactive properties are clear DNA, there are thousands of copies 50% ofthe patients, and in nearly 100% of called radicals. They may be harmful of mtDNA in every nucleated cell, each patients with KSS. No other mitochon- when produced in increased amounts and mitochondrion containing 2-10 copies. In drial encephalomyopathies had deletions not neutralized by the normally occurring normal individuals, these copies are iden- (37). In some instances, evolution from a antioxidants. Then leakage may lead to tical, each containing the genes encoding tissue-specific to a multisystem disorder damage of membrane lipids, DNA, pro- 13 proteins, all of which are subunits of (KSS) could be observed, and probably teins, and other macromolecules. the respiratory chain enzyme complexes, could be explained by an increase in the Other sources of radicals are destruc- 22 tRNAs, and 2 rRNAs (for review, see mutated mtDNA fraction with age (38). tion ofcells during chronic (44) refs. 17 and 18). The absence of introns In earlier studies, nuclear rather than with bursts of NO, '02, H202, and OC1; makes mtDNA compact. The only non- mitochondrial mutations were thought degradation of fatty acid and other mol- part of mtDNA is the D (dis- responsible for the above defects. ecules by peroxisomes (45); and by- coding loop in the ratio of placement loop) of about 1000 bp, con- Rather, variation wild-type products of processes acting as defense taining the origin of replication of the H to mutant mtDNA in different tissues mechanisms against toxic substances probably explains the tissue specificity of (44). Exogenous additions to such endog- strand (heavy strand) of the mtDNA and the Sim- the promoters for L- (light strand) and mitochondrial myopathies (39). enous contributors to the load ofoxidants H-strand transcription (19). One of the ilarly, alterations in the tissue distribu- are, e.g., oxides of nitrogen (NO) in cig- tion of the proportion of mutant mtDNA arette smoke, generation ofradicals from fascinating features of mtDNA is that it with time may explain some of the age undergoes mutations 5-10 times faster peroxides promoted by iron and copper dependency. However, disturbances in compounds (Fenton reaction), and prod- than nuclear DNA (20). This increased interactions between nucleus and mito- rate of mutation is due to at least two ucts from normal food intake (46, 47). As chondria were recently reported in fam- a matter of fact, the effects of some factors. (i) There is a lack of histone ilies with mitochondrial disease (CPEO- proteins to protect mtDNA (21). (ii) The anticancer drugs are based on this prin- like syndrome) with autosomal dominant ciple. Thus, Adriamycin targets mitochondria are not efficient in repairing inheritance (for review, see ref. 31). The DNA damage (22). About 90% of oxygen by producing reactive oxygen species. activities of respiratory complexes I and Defense mechanisms try to minimize in the cell is consumed by mitochondria IV were markedly reduced, and there and, as a result, there can be extensive the levels of harmful oxidants and the were multiple deletions of mtDNA span- damage they inflict. Several enzymes oxidative damage to mtDNA (23). ning several kilobases. This autosomal Mitochondria are the only known dominant disease implied mutation in a cytochrome C oxidase source of extranuclear DNA in humans. nucleus-encoded gene (31). The abnor- Since, during egg fertilization, the sperm mal product of this was NADPH contributes only its nuclear DNA to the supposed to interact with mtDNA to oxae zygote (19), the entire mitochondrial gen- cause accumulation of multiple lesions in otype in both males and females is ma- the molecule. This particular area was ternally inherited. Thus, only the moth- recently enriched by similar reports on C\°\H2 OH- H20 ers transmit mtDNA to the children, and CPEO syndromes and multiple deletions only the daughters can transmit mtDNA of mtDNA with autosomal recessive and ,I t t top to the next generation. This inheritance autosomal dominant transmission (39- SUperoxide dismutwe gfddons pero~dkse does not follow Mendelian laws. 42). The next step towards better under- In 1988, a breakthrough in mitochon- standing the pathogenesis of these dis- catalase, peroxidase drial pathophysiology occurred with the eases must include studies of nuclear report of an association of different spo- gene products interfering with mtDNA or FIG. 4. Cellular formation of free radicals. Downloaded by guest on September 23, 2021 8734 Review: Luft Proc. Natl. Acad. Sci. USA 91 (1994) such as superoxide dismutase, catalase, progressively with age in human skeletal ucts of lipid hydroperoxide breakdown and glutathione peroxidase are part of muscle and liver (62, 63). In addition, are responsible for the modification of these mechanisms. The body also has evidence has been presented for age- LDL apoprotein. Aldehyde-modified apo- developed natural lipophilic and hydro- related changes in coenzyme Q levels in lipoprotein B alters receptor affinity and, phobic antioxidants: E, the qui- several tissue: by Beyer et al. (64) in rats, therefore, is subjected to endocytosis via nones (coenzyme Q), and carotenoids, and by Kaldn et al. (65) in humans. the scavenger receptor pathway of mac- typically located in membranes and in While more substantial studies are rophages (69) and accumulates (70, 71). lipoproteins. Water-soluble antioxidants needed, these data-concerning mtDNA, This accumulation can initiate foam cell include vitamin C and thiols such as oxidation, and coenzyme Q-seem to fa- formation and the appearance of athero- glutathione. Many of these antioxidants vor the idea that aging may be associated sclerotic plaques (72-74). The oxidationof also are dietary products. The signifi- with a disturbed balance between oxida- LDL may be prevented by endogenous cance ofvitamins Q and E as antioxidants tive and antioxidative forces, leading to a antioxidant compounds, mainly a-tocoph- has gained enormous attention during the decline in oxidative phosphorylation be- erol and coenzyme Q (75). last few years, especially coenzyme Q, low some "organ-specific threshold" and The approach to reduce such an as- located as it is in the electron transport to mtDNA damage. A morphologic con- sumed imbalance has been based on the system by linking complexes I and III of sequence could be the age-related in- general theme that defective energy sup- the respiratory chain. In its reduced form crease in lipofuscin granules, also termed ply-due to lack of substrate and cofac- it serves as an antioxidant, preventing "age pigments" (66). tor and decreased utilization ofoxygen- lipid peroxidation in biological mem- may lead to the progression of various branes and low density lipoproteins Age-Related Degenerative Diseases and myocardial diseases. This approach is (LDL) and, thereby, playing an active Defects in Oxidative Phosphorylation supported by the findings that low levels role in cellular defense against oxidative of C and E, two of the natural damage. Accordingly, coenzyme Q has In a search for diseases possibly connected plasma antioxidants, may contribute to been given to patients suffering from mi- with defects in oxidative phosphorylation the high incidence of ischemic heart dis- tochondrial diseases. and with alterations in mtDNA, it seems ease (76, 77) and that cardiovascular dis- appropriate to look at tissues that are crit- eases are accompanied by low plasma The Aging Process and the Mitochondria ically dependent on a large supply of ATP concentrations of vitamin C, a-tocoph- for their specific functions-e.g., CNS, erol and ,3-carotene (78, 79), and coen- Many diseases related to aging may in- heart and skeletal muscle, kidney, liver, zyme Q (80). The latter appears to protect volve oxygen radicals at some stage in retina, and pancreatic islets. human LDL more efficiently against lipid their development. In these diseases, it In this connection, some degenerative peroxidation than does a-tocopherol has been proposed that mutations of disorders-such as Parkinson disease (81), demonstrating that LDL-associated mtDNA and changes in cellular bioener- and cardiomyopathies-are associated coenzyme Q may be an important anti- getics contribute in some way to the aging with deletions of the mitochondrial ge- risk factor. Again, these studies must be process and to the development of de- nome, in contrast to the classical enceph- considered preliminary. generative diseases. Thus, the capacity alomyopathies (e.g., MERRF, MELAS, . Dilated car- for oxidative phosphorylation declines and LHON), characterized by distinct diomyopathy is the most common cause with age (29) due to accumulation of mutations. Ozawa et al. (67) recently of severe cardiomyopathies in young and defective mtDNA, nuclear DNA, or expanded this knowledge by demonstrat- middle-aged people. Deletions in mtDNA both. ATP production can decline below ing that patients with degenerative disor- in heart muscle from such patients have a level critical for the function ofthe cell. ders (Parkinson disease and dilated or been demonstrated (82, 83). Most of There is evidence that the "normal" ag- hypertrophic cardiomyopathy) and clas- these cardial myopathies are familial ing process is accompanied by damage of sical encephalomyopathies (MERRF and (84), and in some families an X-chromo- molecules, including mtDNA, and that MELAS), which carry some distinct but somal inheritance has been suggested such damage accumulates with age (48- partly overlapping symptoms and pathol- (85). Interestingly, in a patient with fa- 51). A 5-kb common deletion of mtDNA ogies, also carry similar clustering of milial dilated cardiomyopathy (86) was found to accumulate with age in point mutations ofmtDNA. They empha- mtDNA with deletions of different sizes human brain and skeletal muscle (52). size, first, that these patients, while hav- made up about 50%o of total mtDNA in Furthermore, diseases associated with ing phenotypically different disorders, heart muscle. This suggests the presence alterations in mtDNA progress with age, belong to the same mtDNA gene family of some nuclear gene defect leading to and this progression is associated with an and, second, that not one particular mu- multiple mtDNA deletions (see above). increasing proportion of deleted mole- tation but the type and total number of Recently, a rapidly escalating number cules. In heart muscle, mtDNA dele- mutations of a patient is an important of reports have appeared on attempts to tions-especially a 3.6-kb deletion- factor for the expression of the disease. treat "cardiomyopathy" with com- have been shown to accumulate after 35 Brown et al. (68) supported this sugges- pounds with antioxidant action, in par- years of age (53-55), as has a 3-kb dele- tion by reporting on synergistically inter- ticular coenzyme Q (87-92). While some tion in skeletal muscle (56). In addition, acting mutations of mtDNA in LHON, of the reports may be promising, such the concentration of mitochondrial indicating that the clinical manifestations treatment is yet to be established. mRNA and rRNA declined with age in rat ofthe disease are the product of an over- The CNS. The CNS derives its energy brain and heart (57) and was associated all decrease in mitochondrial energy pro- almost exclusively from oxidative phos- with a 50% decrease in transcription rate duction rather than a defect in a specific phorylation and thus consumes a large (58). In ischemic hearts, hypoxemic in- mitochondrial enzyme. amount of oxygen. Hydrogen peroxide hibition of oxidative phosphorylation The Cardiovascular System. mtDNA (H202) is a normal by-product of the was accompanied by an increase in deletions and depressed activities of the function of several enzymes of impor- mtDNA damage (59). enzymes in oxidative phosphorylation in tance for the CNS-e.g., monoamine ox- As a sign of the aging process, the aging heart muscle could pave the way for idase and tyrosine hydroxylase-and of number of cytochrome c oxidase-nega- a disturbed balance of oxidation/antioxi- the autooxidation of several endogenous tive skeletal and heart muscle fibers in- dation. The imbalance could lead to free substances (ascorbic acid and catechol- creased with age (60, 61), and enzyme radical-mediated lipid peroxidation, in- amines). Any disturbances in the equilib- activities of complexes I and IV declined cluding that of LDL. The aldehyde prod- rium between oxidation and antioxida- Downloaded by guest on September 23, 2021 Rveview: Luft Proc. NatL. Acad. Sci. USA 91 (1994) 8735 tion in the CNS tissues could disrupt the tion of OH from 02 (99), ultimately lead- creased in the nigrostriatal region of efficiency of electron transport. This ing to degeneration of neurons (100). brains from Parkinson patients (95). The could decrease ATP availability to cellu- Thus, stimulation of receptors for neu- amount of deletion-bearing relative to lar functions in the CNS such as ATP- rotransmitters-as in this case gluta- normal mtDNA in such patients was regulated K channels, Ca2+ pumps, mate-may activate processes in the about 10 times larger than in controls Na+/K+ pumps, exocytosis, and various CNS leading to an imbalance in oxida- (111). Parkinson disease has been sug- phosphorylation processes. tion/antioxidation. This in turn could be gested to appear when the genomes that Another possible process leading to accompanied by cumulative damage to have undergone deletions surpass a cer- oxidative stress in the CNS could involve DNA, proteins, and lipids, and eventu- tain threshold, or the deletions are con- the centrated to a specific neuronal subtype major excitatory neurotransmitter ally to degeneration of neurons. The re- of the striatum (31). glutamate (for review, see ref. 93) (Fig. sults would be especially harmful if, for In addition, is induced 5). There is increasing evidence that glu- some reason, antioxidant defenses are by a specific toxin ofthe substantia nigra, tamate may be a major mediator of oxi- compromised, as during aging. 1-methyl-4-phenyl-1,2,3,6-tetrahydropy- dative stress in the CNS, primarily However, systemic treatment with a ridine (MPTP), a strong inhibitor of through its activation of ionotropic re- variety offree radical scavengers did not NADH-coenzyme Q reductase (complex ceptors, distinguished by specific ago- protect against striatal lesions produced I) and generator of oxygen radicals (112- nists. Activation of glutamate receptors by intracerebral injection of glutamate 114). Treatment with glutamate receptor by these agonists in tissue culture leads to receptor agonists (101, 102). agonists protected against the dopami- neuronal degeneration (94, 95). The pro- Neurodegenerative Diseases. Oxidative nergic degeneration induced by an MPTP cesses include receptor-mediated influx stress, perhaps partly glutamate medi- metabolite (115, 116). These data suggest of Na+ and Ca2+, which brings about a ated, has also been implicated in some a possible link between oxidative stress series of events including initiaition ofthe neurodegenerative diseases. In Parkin- and glutamate neurotransmission in this arachidonic acid cascade, activation of son disease there is degeneration of do- system (93). For a while, emphasis was proteases, and stimulation of NO syn- paminergic neurons projecting into the put on a 5-kb deletion of mtDNA in the thase. The depolarization increases ATP caudate-putamen. The dopaminergic striatum (111), but that could not be con- consumption induced by Na+/K+ system may be at risk for oxidative stress firmed (115-117). ATPase, increasing oxidative phosphor- (103), since the oxidation of catechol- Amyotrophic lateral sclerosis (ALS). ylation with superoxide radicals as a by- amines by monoamine oxidase, which ALS is accompanied by progressive de- product. These radicals, as well as ara- increases with age, is a source of oxygen generation of motor neurons in the brain chidonic acid, enhance the release of radicals (104). Enzyme assays in brains stem and spinal cord. In about 10%o ofthe inhibit its patients, ALS is inherited as an autoso- glutamate and inactivation, from Parkinson patients did reveal a re- mal dominant trait with high penetrance thereby promoting the harmful events duction of complex I activity, especially after the sixth decade (118, 119). There (96, 97). Furthermore, NO released in the in the substantia nigra (105-107), also are some data suggesting that oxidative above process interferes with many observed in blood platelets (108) and stress and activation of glutamate-gated events, including oxidative phosphoryla- skeletal muscle mitochondria (109, 110). cation channels may be involved in ALS tion, with a reduction in ribonucleotide Furthermore, some of the mtDNA- (93). Eleven different missense mutations reductase activity (98) and with forma- encoded subunits of complex I were de- in the gene encoding one form of cyto- solic superoxide dismutase (SOD1)- KAIAMPA Voltage gated responsible for the degradation of the PReceptor channeis toxic superoxide anion O°- to 02 and lecepto, 2+ H20-were observed in families suffer- 2+ Na+Ca Ca ing from the autosomal dominant form of Na Na' Glu Ca ALS (120). In addition, the content of protein carbonyl, a measure of protein oxidation, was elevated in patients with sporadic ALS as compared with con- trols-at least suggesting oxidative stress as a feature of ALS (93). These data,

24- NOS +C 2 while limited, may carry some important Ca -.- -Ca+2+ Arg ~ implications for future therapy in ALS PLA2 Calpain NO (121). 2-Xan DH Huntington disease (HD). HD is an autosomal inherited disorder, character- ized by disturbances in movement and AA XQ progressive dementia and with onset at a mature age. Intrastriatal injection of a

02 '02 glutamate receptor agonist reproduced several aspects of the neuropathology of FIG. 5. Schematic representation ofthe glutamate receptor-mediated processes that may be HD, indicating some dysfunction in the involved in the generation ofoxidative stress. This is a modification ofthe model presented by disposition of excitatory amino acids Coyle and Puttfarcken (93). Glutamate activates the kainic acid/a-amino-3-hydroxy-5-methyl- (122). The levels ofglutamate in cerebro- 4-isoxazolepropionic acid (KA/AMPA) receptor, which results in opening of channels through spinal fluid were reported to be elevated which Na+ and Ca2+ flow. Depolarization activates voltage-gated Ca2+ channels, enabling Ca2+ in HD (123). Pharmacological inhibition influx and thereby increasing cytoplasmatic free Ca2+, [Ca2+]j. Under partially depolarizing of complex I or complex H caused the conditions, Na+ and Ca2+ flow through channels of the N-methyl-D-aspartate (NMDA) recep- same tor. An increase in (Ca2+]i may activate various enzymes such as phospholipase A2 (PLA2), selective pattern ofdegeneration as proteases, and NO synthase (NOS), promoting the formation of -OHy and NO. {OHy is also seen with glutamate receptor agonists produced as a by-product in the increased oxidative phosphorylation, which follows an (124, 125). Neuronal susceptibility to increased ATP consumption by the Na+/K+ ATPase. AA, arachidonic acid; Xan DH, xanthine complex II inhibition increases with age dehydrogenase; XO, xanthine oxidase. in animals, which may be germane to the Downloaded by guest on September 23, 2021 8736 Review: Luft Proc. Natl. Acad. Sci. USA 91 (1994) delayed onset of in There are several lines of evidence sug- tive phosphorylation and its conse- HD (126). The ensuing disruption of the gesting alterations in mtDNA in two of quences could play a significant role in its respiratory chain could lead to impaired the major tissues involved in diabetes, pathophysiology. oxidative phosphorylation. In addition, pancreatic islets and skeletal muscle, abnormal mitochondrial structures and both highly reliant on oxygen. Formation Therapeutic Aspects accumulation of lipofuscin have been of free radicals such as NO and -OH and demonstrated in HD (127). A complex IV alkylation of DNA and proteins also oc- Understanding the mechanisms behind defect in the caudate, but not in the cur in the beta cells of the pancreatic the development of mitochondrial dis- cortex, was found in brains from patients islets, and the inadequately protected mi- eases offers strategies for attempts at with HD (128), and also a complex I tochondrial genome is open to attack their treatment. Possibilities are supple- defect in blood platelet mitochondria from such chemicals. Various diabeto- mentation of cofactors in the respiratory (129). These and other data favor the genic agents could operate by this chain, addition of oxidizable substrates, possible involvement in HD of oxidative route-e.g., interleukin 18, interferon y, and prevention ofoxygen radical damage stress, perhaps in combination with dys- tumor necrosis factor a, alloxan, and to the mitochondria. function of glutamate metabolism. streptozotocin (ref. 136; for review, see Favorable results with antioxidants, Alzheimer disease. Alzheimer disease ref. 137). The action of some of these "4redox therapy," were reported in a pa- is an age-related dementia, characterized agents could be inhibited by antioxidants tient with a severe defect in complex III pathologically by neurofibrillary tangles, in animal models (138-141) as well as in of the respiratory chain (159). Favorable senile plaques, and amyloid deposits in humans (142). Such observations- led results have also been reported in other the CNS. There are indications fordefects Okamoto (143) to suggest that diabetoge- circumstances (for reviews, see refs. 160 in mitochondrial function in this disease: nic agents induce breaks of mtDNA in and 161): e.g., with coenzyme Q and oxidative phosphorylation was not effec- islets, ultimately followed by death of succinate in a patient with KSS and a tively coupled in homogenates of neocor- beta cells. Universal applicability of this complex I defect (162) and with a prom- tex from patients (130); there were hypothesis has been questioned (144). inent complex IV lesion (163); with co- marked reductions in pyruvate dehydro- Gerbitz (137) discusses whether mito- enzyme Q in ocular myopathy (164); and genase in frontal and occipital cortex (131) chondrially encoded peptides can serve with coenzyme Q in five patients with and in complex I activity in blood platelet as MHC-restricted antigens. Some find- KSS and low levels of coenzyme Q in mitochondria from patients (132); and dis- ings point in this direction (145, 146). If serum and the mitochondrial fraction of tinct point mutations of mtDNA were future research verifies this possibility, skeletal muscle (164). Coenzyme Q also reported in brain sections (133). There- autoreactivity would enter the scheme occupies a special place in the attempts to fore, the development of Alzheimer dis- leading to IDDM. normalize oxidation/antioxidation ab- ease to some extent involves components There is already some clinical evidence normalities in age-related disease. Again, of mitochondrial energy production, in- for the involvement of mtDNA in the however, many of the reports on the use cluding degeneration ofsynaptosomes be- development of diabetes. Patients with of coenzyme Q are anecdotal and require cause of impaired energy production of KSS and CPEO (see above) have an substantiation. synaptosomal mitochondria (29). incidence of diabetes several times The rationale for treatment of cardio- On the whole, oxidative stress seems higher than in the general population myopathy with coenzyme Q rests, in to represent one possible pathway- (147-149). The earlier the onset of mito- part, on the finding of myocardial dys- perhaps in part initiated by glutamate- chondrial myopathy in these conditions, function and defective energy supply in leading to neuronal degeneration in a the more frequent was its association biopsy samples from subjects with such manner consistent with the course and with IDDM (150). Also, MELAS and pathology (165). While there are favor- pathology of some degenerative diseases other mitochondrial cytopathies are able reports on administration of coen- of the CNS. However, antioxidants at sometimes associated with diabetes (151) zyme Q in that circumstance (166-169), best provided only partial protection, and and with a point mutation of mtDNA additional studies are required to estab- oxidants can be generated by a number of (152). This makes it likely that alterations lish its possible role in that therapy. mediators independent of glutamate of mtDNA of the beta cells may contrib- Other ways of treating diseases that (134). Furthermore, otherpathologic pro- ute to the development of diabetes. can be attributed to dysfunction of oxi- cesses may be the primary events en- Recently, a systemic 10.4-kb mtDNA dative phosphorylation have been tried hancing the vulnerability to glutamate, deletion was reported in a family with (170-173). One in LHON includes func- such as the amyloid A4 peptide in Alz- maternally transmitted diabetes and sen- tional relocation ofnormal mitochondrial heimer disease (135). These and other sor-neural deafness (153). Subsequently genes to the patient's nucleus so that observations and views demonstrate the an A-to-G transition at nucleotide pair theirprotein products are delivered to the gaps in our knowledge of the specific 3243, a conserved position in the mito- organelle from the cytoplasm. In an- metabolic processes that may promote chondrial gene for tRNA'uR, also has other, myoblasts from patients with mi- oxidative stress at the neuronal level, been reported in families with diabetes tochondrial myopathy have been ex- including glutamate receptor activation (154-156). This mutation leads to impair- planted, and their mutant DNA has been (93). Filling these gaps may lead to strat- ment of mitochondrial transcription ter- replaced with normal DNA. The geno- egies for blocking pathways involved in mination, which causes defects in mito- typically normal muscle cells have then neuronal degeneration. chondrial protein synthesis (157). A sim- been expanded and injected back into the ilar mutation was found in insulin patient's muscle, where they could fuse Diabetes Mellitus antibody-positive subjects, initially diag- to existing myotubes, contributing more nosed as NIDDM, who progressed to normal mtDNA and supplementing mito- Non-insulin-dependent diabetes mellitus IDDM (158). The mutation may be con- chondrial energy production. (NIDDM) is an age-related disease, nected with a variable and progressive which also exhibits features of a degen- decrease in insulin secretory capacity. Conclusions erative disorder. Can an increase in the It is unlikely that "common" NIDDM, incidence of insulin-dependent diabetes constituting about 90%o of the diabetic We can anticipate expansion of the field mellitus (IDDM) be on the basis of envi- population, has its origin in specific mu- of mitochondrial medicine in several di- ronmental exposure or other factors in- tations of mtDNA. However, an age- rections: first, into some age-related dis- volving the mitochondrial genome? related decline in the capacity for oxida- eases so far not approached; second, into Downloaded by guest on September 23, 2021 ReWview: Luft Proc. Natl. Acad. Sci. USA 91 (1994) 8737

areas connected with new concepts in A. M. S., Seibel, P., Ballinger, S. W. & Wal- Biochem. Biophys. Res. Commun. 176, 645- mitochondrial biochemistry and physiol- lace, D. C. (1990) Cell 61, 931-937. 653. 27. Goto, Y., Nowaka, I. & Horai, S. (1990) 59. Ames, B. N. (1989) Mutat. Res. 214, 41-46. ogy-e.g., protein transport via the mi- Nature (London) 348, 651-653. 60. Mfiller-H6cker, J. (1989) Am. J. Pathol. 134, tochondrial membrane. Of great interest 28. Wallace, D. C. (1989) Trends Genet. 5, 9-13. 1167-1173. are in-depth studies aiming at a better 29. Wallace, D. C. (1992) Annu. Rev. Biochem. 61. Muller-Hocker, J. (1990) J. Neurol. Sci. 100, understanding of the processes underly- 61, 1175-1212. 14-21. 30. Grossman, L. I. (1990) Am. J. Hum. Genet. 62. Trounce, I., Byrne, E. & Marzuki, S. (1989) ing the mitochondrial defects and well- 46, 415-417. Lancet 1, 637-639. controlled studies on the place of nutri- 31. Zeviani, M. & DiDonato, S. (1991) Neuro- 63. Yen, T. C., Chen, Y. S., King, K. L., Yeh, tional supplements and replacement ther- musc. Disord. 1, 165-172. S. H. & Wei, Y. H. (1989) Biochem. Biophys. apy with suitable redox compounds in the 32. Lestienne, P. & Ponsat, G. (1988) Lancet i, Res. Commun. 165, 944-1003. 885. 64. Beyer, R. E., Burnett, B. A., Cartwright, amelioration ofdisorders due to deficien- 33. Zeviani, M., Moraes, T., DiMauro, S., Na- K. J., Edington, D. W., Falzon, M. J., Kreit- cies in mitochondrial bioenergetics. kase, H., Bonilla, E., Schon, E. A. & Roland, man, K. R., Kuhn, T. W., Ramp, B. J., Rhee, L. P. (1988) Neurology 38, 1339-1346. S. Y. S., Rosenwasser, M. J., Stein, M. & I am indebted to Drs. Bernard Landau and 34. Saifuddin, N. A., Marzuki, S., Trounce, I. & An, L. C. I. (1985) Mech. Ageing Dev. 32, P. 0. Berggren for their criticism. Byrne, E. (1988) Lancet 1, 1253-1254. 267-281. 35. Jones, D. R., Drachman, D. B. & Hurko, O. 65. Kalen, A., Appelkvist, E.-L. & Dallner, G. (1989) Lancet 1, 393-394. (1989) Lipids 24, 579-584. 1. Luft, R., Ikkos, D., Palmieri, G., Ernster, L. 36. Poulton, J., Deadman,- M. E. & Gardiner, 66. Zhang, J. R. & Sevanian, A. (1991) Biochim. & Afzelius, B. (1962) J. Clin. Invest. 41, 1776- R. M. (1989) Lancet 1, 236-240. Biophys. Acta 1085, 159-166. 1804. 37. Moraes, C. T., DiMauro, S., Zeviani, M., 67. Ozawa, T., Tanaka, M., Sugiyama, S., Ino, 2. DiMauro, S., Schotland, D. L., Lee, C. P., Lombes, A., Shanske, S., Miranda, A. F., H., Ohno, K., Hattori, K., Ohbayashi, T., Ito, Bonilla, E. & Conn, H., Jr. (1972) Trans. Am. Nakase, H., Bonilla, E., Werneck, L. C., T., Deguchi, H., Kawamura, K., Nakana, Y. Acad. Neurol. 66, 265-267. Servidei, S., Nonaka, I., Koga, Y., Spiro, & Hashiba, K. (1991) Biochem. Biophys. Res. 3. DiMauro, S., Bonilla, E., Lee, C. P., Schot- A. J., Keith, A., Brownell, W., Schmidt, B., Commun. 177, 518-525. land, D. L., Scarpa, A. & Coon, H. (1976) J. Schotland, D. J., Zupang, M., DeVivo, D. C., 68. Brown, M. D., Voljavec, A. S., Lott, M. T., Neurol. Sci. 27, 217-232. Schon, A. E. & Rowland, L. P. (1989) N. Torroni, A., Yang, C. C. & Wallace, D. C. 4. Bonilla, E., Schotland, D. L., DiMauro, C. & Engl. J. Med. 320, 1293-1299. (1993) Genetics 130, 163-173. Lee, C. P. (1977) J. Ultrastruct. Res. 58, 1-9. 38. Larsson, N. G.,Holme, E., Kristiansson, B., 69. Sparrow, C. P., Parthasaratly, S. & Steinberg, 5. Nedergaard, J. & Cannon, B. (1992) in Mo- Oldfors, A. & Fulinius, M. (1990) Pediatr. D. (1988) J. Biol. Chem. 263, 504-507. lecular Mechanisms in Bioenergetics, ed. Ern- Res. 28, 131-136. 70. Brown, M. S. & Goldstein, J. L. (1990) J. ster, L. (Elsevier/North Holland, Amster- 39. Poulton, J. (1992) BioEssays 14, 763-768. Hypertens. 8, Suppl. 1, 33-36. dam), pp. 385-420. 40. Yazaki, M., Ohkoshi, N., Kanazawa, I., Ka- 71. Goldstein, J. L. & Brown, M. S. (1987) Cir- 6. Ernster, L. & Luft, R. (1964) in Advances in gava, Y. & Ohta, S. (1989) Biochem. Biophys. culation 76, 504-507. Metabolic Disorders, eds. Levine, R. & Luft, Res. Commun. 164, 1352-1357. 72. Steinberg, D., Berliner, J. A., Burton, G. W., R. (Academic, New York), pp. 95-123. 41. Moraes, C. T., Shanske, S., Tritschler, H. J., Carew, T. E., Chait, A., et al. (1992) Circula- 7. Morgan-Hughes, J. A. (1982) in Skeletal Mus- Aprille, J. R., Andreta, F., Bonilla, E., Schon, tion 85, 2337-2344. cle Pathology, eds. Mastaglia, F. L. & Wal- E. A. & DiMauro, S. (1991) Am. J. Hum. 73. Salonen, J. I., Nyyssonen, K., Korpela, H., ton, J. N. (Churchill Livingstone, Edinburgh), Genet. 48, 492-501. Tuomilehto, J., Seppanen, R. & Salonen, R. pp. 309-339. 42. Soumalainen, A., Majander, A., Hiltia, M., (1992) Circulation 86, 803-811. 8. Spiro, A. J., Moore, C. L., Prineas, J. W., Somer, H., Lbnnqvist, J., Savontaus, M.-L. & 74. Jialal, I. & Grundy, S. M. (1992) J. LipidRes. Strasberg, P. M. & Rapin, I. (1970) Arch. Peltonen, L. (1992) J. Clin. Invest. 90, 61-66. 33, 899-906. Neurol. 23, 103-112. 43. Arnaudo, E., Dalakas, M., Shanske, S., Mo- 75. Esterbauer, H., Wag, G. & Puhl, H. (1993) Br. 9. Blass, J. P., Avigan, J. & Uhlendorf, B. W. raes, C. T., DiMauro, S. & Schon, E. A. Med. Bull. 49, 566-576. (1970) J. Clin. Invest. 49, 423-432. (1990) Lancet 337, 508-510. 76. Gey, K. F. & Puska, P. (1989) Ann. N.Y. 10. French, J. H., Sherard, E. S., Lubell, H., 44. Ames, B. N., Shigenaga, M. K. & Hagen, Acad. Sci. 570, 268-282. Brotz, M. & Moore, C. L. (1972) Arch. Neu- T. M. (1993) Proc. Natl. Acad. Sci. USA 90, 77. Riemersma, R. A., Wood, D. A., McIntyre, rol. 26, 229-244. 7915-7922. C. C. A., Elton, R., Gey, K. F. & Oliver, 11. Engel, A. G. & Angelini, C. (1973) Science 45. Kasai, H., Okada, Y., Nishimura, S., Rao, M. F. (1989) Ann. N. Y. Acad. Sci. 570, 291- 179, 899-902. M. S. & Reddy, J. K. (1989) Cancer Res. 49, 295. 12. DiMauro, S. & Melis-DiMauro, P. M. (1973) 2603-2605. 78. Gaziano, J. M., Manson, J. E., Buring, J. E. Science 182, 929-931. 46. Ames, B. N., Profet, M. & Gould, L. S. (1990) & Hennekens, C. H. (1992) Ann. N. Y. Acad. 13. Scholte, H. R. (1988) J. Bioenerg. Biomembr. Proc. Nati. Acad. Sci. USA 87, 7777-7781. Sci. 669, 249-259. 20, 161-191. 47. Gold, L. S., Stone, T. H., Stern, B. R., Man- 79. Enstrom, J. E., Kanim, L. E. & Klein, M. A. 14. Nass, S. & Nass, M. M. K. (1963)J. CellBiol. ley, N. B. & Ames, B. N. (1992) Science 258, (1992) Epidemiology 3, 194-202. 19, 613-629. 261-265. 80. Karlsson, J., Diamant, B. & Theorell, H. 15. Schatz, G. E., Haslbrunner, E. & Tuppy, H. 48. Ames, B. N. & Shigenaga, M. K. (1992) Ann. (1992) in Vitamin E: Biochemistry and Clinical (1964) Biochem. Biophys. Res. Commun. 15, N.Y. Acad. Sci. 663, 85-96. Applications, eds. Packer, L. & Fuchs, J. 127-132. 49. Sai, K., Takagi, A., Umemura, T., Hasegawa, (Dekker, New York), pp. 473-493. 16. Anderson, S., Bankier, A. T., Barrel, B. G., R. & Kurokawa, Y. (1992) J. Environ. Pathol. 81. Stocker, R., Bowry, V. W. & Frei, B. (1991) deBruin, M. H. L., Coulson, A., Drouin, J., Toxicol. Oncol. 2, 139-143. Proc. Natl. Acad. Sci. USA 88, 1646-1650. Speron, I. C., Nierlich, D. P., Roe, B. A., 50. Stadtman, E. R. (1992) Science 257, 1220- 82. Ozawa, T., Tanaka, M., Sugiyama, S., Hat- Sanger, F., Schreier, P. H., Smith, A. J. H., 1224. tori, K., Ito, T., Ohno, K., Takahashi, A., Staden, R. & Young, I. G. (1981) Nature (Lon- 51. Linnane, A. W., Marzuki, S., Ozawa, T. & Sato, W., Takuda, G., Mayumi, B., Yama- don) 290, 457-465. Tanaka, M. (1989) Lancet 1, 642-645. moto, K., Adachu, K., Koga, Y. & Toshima, 17. Attardi, G., Chomyn, A., King, M. P., Kruse, 52. Cooper, J. M., Mann, V. M. & Shapira, H. (1990) Biochem. Biophys. Res. Commun. B., Polosa, P. L. & Murdter, N. N. (1990) A. H. V. (1992) J. Neurol. Sci. 113, 91-98. 170, 830-836. Biochem. Soc. Trans. 18, 509-513. 53. Cortopassi, G. A. & Arnheim, N. (1990) Nu- 83. Hattori, K., Ogawa, T., Kondo, T., Mochi- 18. Clayton, D. A. (1991) Annu. Rev. Cell Biol. 7, cleic Acids Res. 18, 6027-6933. zuki, M., Tanaku, M., Sugyyama, S., Ito, T., 453-478. 54. Hattori, K., Tanaka, M., Sugiyama, S., Oba- Satake, T. & Ozawa, T. (1991) Am. Heart J. 19. Wallace, D. C. (1989) Cytogenet. Cell Genet. yashi, T., Ito, T., Satake, T., Hanaki, Y., 122, 866-869. 51, 612-621. Asai, J., Nagaas, M. & Ozawa, T. (1991) Am. 84. Michels, V. V., Moll, P. P., Miller, F. A., 20. Schoffner, J. M. & Wallace, D. C. (1990) Adv. Heart J. 121, 1735-1742. Tajok, A. J., Chu, J. S., Driscoll, D. J., Bur- Hum. Genet. 19, 267-330. 55. Corral-Debrinski, M., Stepien, G., Shoffner, nett, J. C., Rodeheffer, R. J., Chesebro, J. H. 21. Richter, C. (1988) FEBS Lett. 241, 1-15. J. M., Lott, M. T., Kantor, K. & Wallace, & Tazelaar, H. D. (1992)N. Engl. J. Med. 326, 22. Clayton, D. A. (1982) Cell 28, 693-705. D. C. (1991) J. Am. Med. Assoc. 226, 1812- 77-82. 23. Richter, C., Park, J.-W. & Ames, B. N. (1988) 1816. 85. Berko, B. A. & Swift, M. (1987) N. Engl. J. Proc. Natl. Acad. Sci. USA 85, 6465-6467. 56. Katayama, M., Tanaka, M., Yamamoto, H., Med. 316, 1186-1191. 24. Holt, I. J., Harding, A. E. & Morgan-Hughes, Obayashi, T., Mimura, Y. & Ozawa, T. (1991) 86. Soumalainen, A., Paetan, A., Leinonen, H., J. A. (1988) Nature (London) 331, 717-719. Biochem. Int. 25, 47-56. Majander, A., Peltonen, L. & Somer, H. 25. Wallace, D. C., Singh, G., Lott, M. T., 57. Gadaleta, M. N., Petruzella, V., Renis, M., (1992) Lancet 340, 1319-1320. Hodge, J. A., Schurr, T. G., Lezza, A. M. S., Fracasso, F. & Cantalore, P. (1990) Eur. J. 87. Nayler, W. G. (1980) in Biomedical and Clin- Elsas, I. M. J. & Nikoskelainen, E. (1988) Biochem. 187, 501-506. ical Aspects ofCoenzyme Q, eds. Folkers, K. Science 242, 1427-1430. 58. Fernandez-Silva, P., Petruzella, V., Fracasso, & Ito, Y. (Elsevier/North Holland, Amster- 26. Shoffner, J. M., Lott, M. T., Lezza, F., Gadaleta, M. N. & Cantalore, P. (1991) dam), pp. 409-425. Downloaded by guest on September 23, 2021 8738 Review: Luft Proc. Natl. Acad. Sci. USA 91 (1994)

88. Ohhara, H., Kanaide, H., Yoshimura, R., man, P.-A. & Wachtel, H. (1991) Nature (Lon- 148. Lakin, M. & Locke, S. (1961) Diabetes 10, Okada, M. & Nakamura, M. (1981) J. Mol. don) 349, 414-418. 228-231. Cardiol. 13, 65. 117. Lestienne, P., Nelson, J., Riederer, P., Jel- 149. Tanabe, Y., Migamoto, S., Kinoshita, Y., 89. Sunamori, M., Tanaka, H., Maruyama, T., linger, K. & Reichmann, H. (1990) J. Neuro- Yamada, S., Sasaki, N., Makino, E. & Naka- Sultan, I., Sakamoto, T. & Suzuki, A. (1991) chem. 55, 1810-1812. jima, H. (1988) Eur. Neurol. 28, 34-38. Cardiovasc. Drugs 5, 297-300. 118. Mulder, D. W., Kurland, L. T., Offord, K. P. 150. Enter, C., Muller-Hocker, J., Ziers, S., Kur- 90. Hiasa, Y., Ishida, T., Maeda, T., Iwano, K., & Beard, C. M. (1986) Neurology 36, 511-517. lemann, G., Pongratz, D., F6rster, C., Ober- Aichara, T. & Mori, H. (1984) in Biomedical 119. Horton, W. A., Eldridge, R. & Brody, J. A. maier-Kuser, B. & Gerbitz, K. D. (1991) and Clinical Aspects of Coenzyme Q, eds. (1976) Neurology 26, 460-464. Hum. Genet. 88, 233-236. Folkers, K. & Yamamura, Y. (Elsevier, 120. Rosen, D. R., Siddique, T., Patterson, D., 151. Rotig, A., Bessis, I. L., Romero, N., Cormier, Amsterdam), pp. 291-301. Figlewicz, D. A., Sapp, P., et al. (1993) Na- V., Sandubray, J. M., Narcy, P., Lenoir, G., 91. Kamikawa, T., Kobayashi, A., Yamashita, T., ture (London) 362, 59-62. Rustin, P. & Munnich, A. (1992) Am. J. Hum. Hayashi, H. & Yamazaki, N. (1985) Am. J. 121. Shoulson, I. (1992) Ann. N. Y. Acad. Sci. 648, Genet. 50, 364-370. Cardiol. 56, 247-254. 37-41. 152. Got, Y.-I., Nonaka, I. & Horai, S. (1990) 92. Schardt, F., Wetzel, D., Schiess, W. & Toda, 122. Coyle, J. T. & Schwarz, R. (1976) Nature Nature (London) 348, 651-653. K. (1985) in Biomedical and Clinical Aspects (London) 263, 244-246. 153. Ballinger, S. W., Shoffner, J. M., Hedaya, of Coenzyme Q, eds. Folkers, K. & Yama- 123. Percy, T. L. & Hansen, S. (1990) Neurology E. V., Trounce, I., Polak, M. A., Koontz, mura, Y. (Elsevier, Amsterdam), pp. 385-394. 40, 20-24. D. A. & Wallace, D. C. (1992) Nat. Genet. 1, 93. T. 11-15. Coyle, J. & Puttfarcken, P. S. (1993) Sci- 124. Bazzet, T. J., Becker, J. B., Kaatz, K. W. & 154. van den Ouweland, J. M. V., Lemkes, H. & ence 262, 689-695. Albin, R. L. (1993) Exp. Neurol. 120,177-185. Massen, J. A. (1991) Nucleic Acids Res. 19, 94. Kato, K., Puttfarcken, P. S., Lyons, W. E. & 125. Novelli, A., Reilly, J. A., Lysko, P. G. & 1962. Coyle, J. T. (1991) Pharmacol. Exp. Ther. 256, Henneberry, R. C. (1988) Brain Res. 451, 205- 155. Reardon, W., Ross, R. J. M., Sweeney, 402-411. 212. M. G., Luxon, L., Pembrey, M. E., Harding, 95. Choi, D. W., Maulucci-Gedde, C. & Krieg- 126. Brouillet, E., Jenkins, B. G., Hyman, B. T., A. E. & Trembath, R. C. (1992) Lancet 340, stein, A. R. (1987) J. Neurosci. 7, 357-368. Ferrante, R. J., Kowall, N. W., Srivastava, 1376-1379. 96. Pellegrini-Giampietro, D., Cherici, G., Alesi- R., Roy, D. S., Rosen, B. R. & Beal, M. F. 156. Katagori, H., Asano, T., Ishihara, K., Inuki, ani, M., Carla, V. & Moroni, F. (1988) J. (1993) J. Neurochem. 60, 356-360. K., Anai, M., Yamanouchi, T., Tsukuda, K., Neurochem. 51, 1960-1963. 127. Tellez-Nagel, I., Johnson, A. B. & Terry, Kikuchi, M., Kitaoka, H., Ohsawa, N., Ysaki, 97. Williams, J. H., Errington, M. L., Lynch, R. D. (1973) J. Neuropathol. Exp. Neurol. 33, Y. & Oka, Y. (1994) Diabetologia 37, 504-510. M. A. & Bliss, T. V. (1989) Nature (London) 308-332. 157. Hess, J. F., Parisi, M. A., Bennett, J. L. & 341, 739-742. 128. Brennan, W. A., Jr., Bird, E. D. & Aprille, Clayton, D. A. (1991) Nature (London) 351, 98. Moncada, S., Palmer, R. M. & Higgs, E. A. J. R. (1985) J. Neurochem. 44, 1948-1950. 236-239. (1991) Pharmacol. Rev. 43, 109-142. 129. Parker, W. D., Jr., Boyson, S. J., Luder, 158. Oka, Y., Katagiri, H., Yazaki, Y., Murase, T. 99. Beckman, J. S., Beckman, T. W., Chen, J., A. S. & Parks, J. K. (1990) Neurology 40, & Kobayaski, T. (1993) Lancet 342, 527-528. Marshall, P. A. & Freeman, B. A. (1990) 123-134. 159. Eleff, S., Kensaway, N. G., Buist, N. R. M., Proc. Natl. Acad. Sci. USA 87, 1620-1624. 130. Sims, N. R., Finegan, J. M., Blass, J. P., Bo- Darley-Usmar, V. M., Capaldi, R. A., Bank, 100. Dawson, T. M., Dawson, V. L. & Snyder, wen, D. M. & Neary, D. (1987) Brain Res. W. J. & Chance, B. (1984) Proc. Natl. Acad. S. H. (1992) Ann. Neurol. 32, 297-311. 436, 30-38. Sci. USA 81, 3529-3533. 101. Miyamoto, M. & Coyle, J. T. (1990) Exp. 131. Shen, K.-F., Kim, Y.-T., Blass, J. P. & Wek- 160. Shoffner, J. M. & Wallace, D. C. (1990) Adv. Neurol. 108, 38-45. sler, M. E. (1985) Ann. Neurol. 17, 444-449. Hum. Genet. 19, 267-330. 102. Beal, M. F., Kowall, N. W., Schwartz, K. J., 132. Parker, W. D., Jr., Filley, C. M. & Parks, 161. Nagley, P., Zang, C., Martinus, R. D., Vail- Ferrante, R. J. & Martin, J. B. (1988) J. Neu- J. K. (1990) Neurology 40, 1302-1303. lant, F. & Linnane, A. W. (1993) in Mitochon- rosci. 8, 3901-3908. 133. Lin, F. H., Lin, R. & Wiesniewski, H. M. drial DNA in Human Pathology, eds. Di- 103. Fahn, F. & Cohen, G. (1992) Ann. Neurol. 32, (1992) Biochem. Biophys. Res. Commun. 182, Mauro, S. & Wallace, D. C. (Raven, New 804-812. 238-246. York), pp. 137-157. 104. Cohen, G. & Spina, M. B. (1989)Ann. Neurol. 134. Siesjo, B. (1992) J. Neurosurg. 77, 337-354. 162. Shoffner, J. M., Lott, M. T., Voljavec, A. S., 26, 689-690. 135. Koh, J., Yang, L. & Cotman, C. W. (1990) Soueidan, S. A., Costigan, D. A. & Wallace, 105. Mizuno, Y., Ohta, S., Tanaka, M., Takamiya, Brain Res. 533, 315-320. D. C. (1989) Proc. Natl. Acad. Sci. USA 86, S., Suzuki, K., Sato, T., Oya, H., Dzawa, T. 136. Richter, C., Park, J. W. & Ames, B. N. (1988) 7952-7956. & Kagawa, Y. (1989) Biochem. Biophys. Res. Proc. Natl. Acad. Sci. USA 85, 6465-6467. 163. Jinnai, K., Yamada, H., Kanada, F., Masui, Commun. 163, 1450-1455. 137. Gerbitz, K.-D. (1992) Diabetologia 35, 1181- Y., Tanaka, M., Ozawa, T. & Fujita, T. (1990) 106. Schapira, A. H., Cooper, J. M., Dexter, D., 1186. Eur. Neurol. 30, 56-60. Jenner, P., Clark, J. B. & Marsden, C. D. 138. LeDoux, S. P., Hall, C. R., Forbes, P. M., 164. Ogasahara, S., Nischikawa, Y., Yorifuji, S., (1989) Lancet i, 1269. Patton, N. J. & Wilson, G. L. (1988) Diabetes Soga, F., Nakamura, Y., Takahashi, M., Hash- 107. Schapira, A. H. V., Cooper, J. M., Dexter, 37, 1015-1019. imoto, S., Kono, N. & Tarni, S. (1986) Neurol- D., Jenner, P., Clark, J. B. & Marsden, C. D. 139. Nomikos, I. N., Wang, Y. & Lofferty, K. J. ogy 36, 45-53. (1990) J. Neurochem. 54, 823-827. (1989) Immunol. Cell Biol. 67, 85-87. 165. Mortensen, S. A. (1993) Clin. Invest. 71, 116- 108. Parker, W. D., Jr., Boyson, S. J. & Parks, 140. Rabinowitch, A., Suarez, W. L., Thomas, 123. J. K. (1989) Ann. Neurol. 26, 719-723. P. D., Strynadka, K. & Simpson, I. (1992) 166. Mortensen, S. A., Vadhanavikit, S., Baan- 109. Bindoff, L. A., Birch-Machin, M. A., Cart- Diabetologia 34, 409-413. drup, V. & Folkers, K. (1985) Drug Exp. Clin. lidge, N. E. F., Parker, W. D., Jr., & Furn- 141. Heineke, E. W., Johnson, M. B., Dillbergar, Res. 8, 581-593. ball, D. M. (1991) J. Neurol. Sci. 104, 203- J. E. & Robinson, K. M. (1993) Diabetes 42, 167. Langsjoen, P. H., Vadhanavikit, S. & Folk- 208. 1721-1730. ers, K. (1985) Drug Exp. Clin. Res. 8, 577-579. 110. Shoffner, J. M., Watts, R. L., Juncos, J. L., 142. Eliott, R. B. & Chase, H. P. (1991) Diabeto- 168. Langsjoen, P. H., Vadhanavikit, S. & Folk- Torroni, A. & Wallace, C. D. (1991) Ann. logia 34, 362-365. ers, K. (1985) Proc. Natl. Acad. Sci. USA 82, Neurol. 30, 332-339. 143. Okamoto, H. (1990) in The Molecular Biology 4240-4244. 111. Ozawa, T., Tanaka, M., Ikebe, S., Ohno, K., of the Islets ofLangerhans, ed. Okamoto, H. 169. Langsjoen, P. H. & Folkers, K. (1990) Am. J. Kondon, T. & Mizuno, Y. (1990) Biochem. (Cambridge Univ. Press, Cambridge, U.K.), Cardiol. 65, 521-523. Biophys. Res. Commun. 172, 483-489. pp. 209-231. 170. Partridge, T. A. (1991) Muscle 14, 197- 112. Langston, J. W., Ballard, P., Tetrud, J. W. & 144. Eizirik, D. L., Sandler, S., Ahnstrom, G. & 212. Irwin, I. (1983) Science 219, 979-980. Welsh, M. (1991) Biochem. Pharmacol. 42, 171. Law, R. H. P., Farrell, L. B., Nero, D., De- 113. Nicklas, W. J., Vyas, I. & Heikkila, R. E. 2275-2282. venish, R. J. & Nagley, P. (1988) FEBS Lett. (1985) Life Sci. 36, 2503-2508. 145. Loveland, B., Wang, C. R., Yonegawa, H., 236, 501-505. 114. Ballard, P. A., Tetrud, J. W. & Langston, Hermel, E. & Fischer-Lindahl, K. (1990) Cell 172. Nagley, P. & Devenish, J. (1989) Trends Bio- J. W. (1985) Neurology 35, 949-956. 60, 971-980. chem. Sci. 14, 31-35. 115. Schapira, A. H. V., Holt, I. J., Sweeney, M., 146. Klinkhammer, C., Popowa, P. & Gleichmann, 173. Lander, E. S. & Lodish, H. (1990) Cell 61, Harding, A. E., Jenner, P. & Marsden, C. D. H. (1988) Diabetes 37, 74-80. 925-926. (1990) Movement Disord. 5, 294-297. 147. Ouada, A., Ziers, S. & Klingmfiller, D. (1988) 174. Wallace, D. C. (1994) Proc. Natl. Acad. Sci. 116. Turski, L., Bresler, K., Rettig, K.-J., Losch- Klin. Wochenschr. 66, Suppl. 13, 34-38. USA 91, 8739-8746. Downloaded by guest on September 23, 2021

Top View