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An evaluation of the role of mitochondria in neurodegenerative diseases: mitochondrial mutations and oxidative pathology, protective nuclear responses, and cell death in neurodegeneration

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Abstract

There is mounting evidence for mitochondrial involvement in neurodegenerative diseases including Alzheimer's and Parkinson's disease and amyotrophic lateral sclerosis. Mitochondrial DNA mutations, whether inherited or acquired, lead to impaired electron transport chain (ETC) functioning. Impaired electron transport, in turn, leads to decreased ATP production, formation of damaging free-radicals, and altered calcium handling. These toxic consequences of ETC dysfunction lead to further mitochondrial damage including oxidation of mitochondrial DNA, proteins, and lipids, and opening of the mitochondrial permeability transition pore, an event linked to cell death in numerous model systems. Although protective nuclear responses such as antioxidant enzymes and bcl-2 may be induced to combat these pathological changes, such a vicious cycle of increasing oxidative damage may insidiously damage neurons over a period of years, eventually leading to neuronal cell death. This hypothesis, a synthesis of the mitochondrial mutations and oxidative stress hypotheses of neurodegeneration, is readily tested experimentally, and clearly points out many potential therapeutic targets for preventing or ameliorating these diseases.

Introduction

The first hint that mitochondria might play a role in human disease did not emerge until halfway through this century. In 1958, a Swedish patient was identified who had symptoms of severe perspiration, polydipsia, polyphagia, weight loss, and weakness [128]. She had been treated previously for hyperthyroidism, resulting in minimal improvement. Laboratory studies showed a basal metabolic rate 200% of normal, very low weight (37 kg), and elevated basal temperature reaching over 38°C at times [128]. Biochemical studies revealed that she had a near-maximal respiratory rate in the presence of substrate without ADP and Pi, yet a normal P/O ratio in the presence of ADP and Pi. This, along with a high ATPase activity which was insensitive to oligomycin (which inhibits respiration tightly coupled to oxidative phosphorylation but not respiration in uncoupled mitochondria), indicated that the patient had a partially uncoupled respiration. These findings accounted for her generation of excessive heat and high calorie consumption [128]. Although the primary etiologic event in Luft's disease remains to be identified, the disease is associated with spontaneous release of mitochondrial calcium stores, which may lead to abnormal calcium cycling and thereby sustained stimulation of respiration and loose coupling 60, 129.

The discovery of Luft's disease unveiled a previously overlooked role of mitochondria in human disease. This cleared the path for fertile explorations in the field of mitochondrial pathology. Since the 1960s, over 120 human mitochondrial diseases have been discovered [129]. Most of these involve selective populations in the central nervous system (CNS) or skeletal muscle system, both of which consist of postmitotic, highly energy-dependent cells. Many of these diseases have been associated with specific, inherited mitochondrial DNA (mtDNA) mutations and accompanying electron transport chain (ETC) deficiencies. Hence, these diseases may be systemic yet only affect certain specific regions—and certain cell populations—of the body.

The brain is acutely dependent on energy supplies for normal functioning [200]. Mitochondria are the intracellular founts of the brain's energy supplies. It is becoming clear that subtle functional alterations in these essential cellular energy dynamos can lead to insidious pathological changes in neurons 10, 11, 27, 57, 65, 167, 171, 238, 239, 240. MtDNA mutations and pathological free radical reactions, amongst other things, may damage mitochondria and decrease ETC activity. Impaired electron transport, in turn, in addition to the obvious impairment in ATP production, also leads to diversion of electrons from their normal ETC recipients and further formation of damaging free-radicals. The cell detoxifies free radicals via its antioxidant defense system (Fig. 1), which includes the antioxidant enzymes (AOEs) superoxide dismutase (SOD), glutathione peroxidase (GPX), glutathione reductase (GRD), and catalase (CAT). As the AOEs are relatively deficient in the brain 135, 137, a vicious cycle of increasing oxidative damage may slowly damage neurons over a period of years, leading to the eventual neuronal cell death characteristic of the sporadic, age-related neurodegenerative diseases.

Mitochondrial-derived pathological free radicals have been implicated in numerous diseases and in the aging process itself 10, 11, 27, 64, 65, 84, 85, 86, 87, 112, 117, 175, 179, 186, 212. The human CNS is relatively deficient in oxidative defenses 135, 137, rendering it more susceptible to reactive oxygen species (ROS)-induced damage. Oxidative stress has been implicated in the major neurodegenerative diseases—Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Each of these diseases exhibits evidence of both ETC impairment and free radical-mediated cellular damage 10, 11, 27, 87, 108, 158, 167, 168, 169, 170, 171, 238, 239, 240.

A dramatic example of the potential fundamental role of free-radicals in neurodegeneration is demonstrated by gain of function mutations in the CuZn superoxide dismutase (CuZn SOD or SOD1) gene in a number of familial ALS kindreds 6, 15, 199, 261, 268. These mutations may lead the SOD1 enzyme to generate excessive peroxynitrite ions (OONO) and hydroxyl radicals (OH), perhaps the most toxic free-radical species known. These systemic, inherited free radical-generating mutations selectively affect CNS motor neurons for undetermined reasons.

Although not the only factors involved in cell death in neurodegeneration, free radicals nonetheless seem to make a major contribution to neuronal damage and eventual death. It is hypothesized that ETC defects are the primary etiologic events in most cases of these diseases 167, 168, 169, 170, 171, 238, 239, 240. Yet, it may be that free radical-mediated damage is the mechanism by which these defects eventually lead to cell death. There is ample evidence for free-radical-mediated damage in these diseases 10, 27, 59, 65, 87, 112, 194, 218, and antioxidants show promise in preventing and/or treating these diseases 10, 12, 81, 83, 86, 204, 209.

The role of mitochondrial genetics in neurodegenerative diseases is a topic which deserves its own comprehensive review. However, because of its fundamental relevance to the mitochondrial hypothesis of neurodegeneration, a brief overview is called for. It is becoming increasingly clear that the mitochondrial genome may play an essential role in neurodegenerative diseases. In 1963, it was first reported by Nass and Nass that mitochondria contain their own genome [149]. The mitochondrial genome is circular, and does not conform to the universal genetic code (a few of the codons in the mitochondrial genome have a different interpretation than they do in all other known living cells), consistent with its apparently independent, prokaryote-like origins. Also unique to mtDNA is that it is passed exclusively through the mother, and may exist in many different copies in the ovum [92]. The existence of different copies of the same mitochondrial genes within a single cell is known as heteroplasmy. Heteroplasmy may account for closely related individuals having quite distinct phenotypes, as the percentage of mutated mtDNA copies present in a given egg cell may vary widely. These factors may lead to an inheritance pattern of mitochondrial diseases which appears to be sporadic yet is truly maternal inheritance 167, 262.

It was not until 1988 that mtDNA mutations were discovered in human diseases 90, 252. Since then, mtDNA mutations have been found in many other diseases 129, 254. The inheritance of late onset neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases, appears to be sporadic. However, biochemical evidence has accumulated that the mitochondrial ETC is defective in these diseases. Specifically, NADH: ubiquinone oxidoreductase, or complex I, of the ETC is defective in PD 11, 23, 25, 131, 147, 168, 238; cytochrome c oxidase (COX), or complex IV, is defective in AD 108, 146, 169, 170, 171, 239. These ETC defects may arise from mutated and oxidatively damaged mtDNA in sporadic PD 53, 94, 95, 162, 238, 254and sporadic AD 51, 138, 239, 254and may be the primary genetic basis of the sporadic forms of these diseases. That the pathogenesis of these defects is mitochondrial in origin is supported by the results of experiments with cytoplasmic hybrid, or `cybrid', cells 238, 239, which recapitulate the ETC defects present in disease patients. These cybrids are created by the transfer of mtDNA to clonal neuronal-like cells which have been depleted of their endogenous mtDNA by long-term, low concentration ethidium bromide treatment (Fig. 2). This system allows investigators to isolate the role of mtDNA in cellular pathology.

Section snippets

How impaired electron transport generates free-radicals

The primary source of free radicals in neurodegenerative diseases is controversial; however, there is mounting evidence that impaired electron transport activity is integral to these diseases. ETC defects can act as free radical generators by blocking the normal passage of electrons down the chain and their ultimate reduction of molecular oxygen to water. It is well established that inhibition of the ETC generates free radicals: for example, the complex I inhibitors rotenone and N

How specific, systemic ETC defects lead to selective neuronal vulnerability

A fundamental question that challenges any hypothesis of neurodegeneration is why specific cell populations are affected. In the case of the mitochondrial mutations hypothesis, the fundamental question is how specific, systemic ETC defects lead to selective neuronal cell death. There is now a wealth of evidence implicating elevated free radicals, enhanced sensitivity to excitotoxicity, and altered Ca2+-buffering as cytotoxic consequences of ETC dysfunction 10, 11, 33, 65, 144, 174, 175, 176, 195

Mitochondrial-derived ROS as signaling molecules

Free radicals are being recognized as not simply damaging oxidizing species, but also as small signaling molecules [237]. The best example of this is NO, which has been clearly shown to play a role in neurotransmission and neuromodulation 29, 77, in addition to its relaxation of smooth muscle and inhibition of platelet aggregation [93]. Various oxidants have been shown to stimulate Ca2+ signaling and protein phosphorylation, which are known to be widely important in activating biological

The mitochondrial permeability transition pore

A potentially central factor in cell death in neurodegneration, which has heretofore been largely ignored in this context, is the mitochondrial transition pore. The MTP is a nonselective, high conductance channel that spans the inner and outer mitochondrial membranes 19, 20, 22, 276. This channel has been shown to be involved in oxidant-induced mitochondrial large-amplitude swelling 19, 20, 40, 115, 116, 276, Ca2+ release 19, 21, 164, 176, 195, 211, and cell death 132, 133, 153, 154, 174, 175,

Nuclear responses to mitochondrial oxidative stress-associated signals: antioxidant enzymes

The AOEs are all nuclear-encoded ROS-detoxifying enzymes which act to protect the cell from oxidative damage. These enzymes may be essential for cellular survival in conditions such as neurodegenerative diseases characterized by elevated oxidative stress. Although it might be expected that the AOEs would be elevated in neurodegenerative diseases such as Alzheimer's and Parkinson's, the experimental results are ambiguous and contradictory. In either case, impairment of these nuclear-encoded

Status of the mitochondrial hypothesis of neurodegeneration

The research to date has not demonstrated conclusively a heritable mitochondrial origin for sporadic AD, PD, or ALS. Significant and prevalent mtDNA mutations have not been identified in these populations as of yet. It is extremely important for the mitochondrial mutations hypothesis that such mutations be discovered. Although it might be seen as a straightforward sequencing job, significant hurdles to large-scale screening have been encountered, including confounding by nuclear pseudogenes 58,

Acknowledgements

JPB is supported by NS35325 and NS34299. DSC is supported by the University of Virginia Medical Scientist Training Program. We would like to thank Drs. J.B. Tuttle, W.D. Parker, Jr., and S.R. Vandenberg for critiquing an earlier version of this manuscript. We would also like to thank Drs. R.H. Swerdlow and W.D. Parker, Jr. for inspiring much of this work.

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