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Role of Mitochondria Mutations in Neurodegenerative Diseases
Posted on: October 14, 2003

Over the last decade, the underlying genetic bases of several neurodegenerative disorders, including Huntington disease (HD), Friedreich ataxia (FRDA), hereditary spastic paraplegia, and rare familial forms of Parkinson disease (PD), Alzheimer disease (AD), and amyotrophic lateral sclerosis (ALS), have been identified. However, the etiologies of sporadic AD, PD, and ALS, which are among the most common neurodegenerative diseases, are still unclear, as are the pathogenic mechanisms giving rise to the various, and often highly stereotypical, clinical features of these diseases. Despite the differential clinical features of the various neurodegenerative disorders, the fact that neurons are highly dependent on oxidative energy metabolism has suggested a unified pathogenetic mechanism of neurodegeneration, based on an underlying dysfunction in mitochondrial energy metabolism.

Mitochondria are the seat of a number of important cellular functions, including essential pathways of intermediate metabolism, amino acid biosynthesis, fatty acid oxidation, steroid metabolism, and apoptosis. Of key importance to our discussion here is the role of mitochondria in oxidative energy metabolism. Oxidative phosphorylation (OXPHOS) generates most of the cell's ATP, and any impairment of the organelle's ability to produce energy can have catastrophic consequences, not only due to the primary loss of ATP, but also due to indirect impairment of "downstream" functions, such as the maintenance of organellar and cellular calcium homeostasis. Moreover, deficient mitochondrial metabolism may generate reactive oxygen species (ROS) that can wreak havoc in the cell. It is for these reasons that mitochondrial dysfunction is such an attractive candidate for an "executioner's" role in neuronal degeneration.

The mitochondrion is the only organelle in the cell, aside from the nucleus, that contains its own genome and genetic machinery. The human mitochondrial genome is a tiny 16.6-kb circle of double-stranded mitochondrial DNA (mtDNA) (Fig. 1).


Fig. 1. Map of the human mitochondrial genome. Polypeptide-coding genes (boldface) are outside the circle and specify seven subunits of NADH dehydrogenase-coenzyme Q oxidoreductase (ND), one subunit of coenzyme Q-cytochrome c oxidoreductase (Cyt b), three subunits of cytochrome c oxidase (CCO), and two subunits of ATP synthase (A) (see also Fig. 2). Protein synthesis genes (12S and 16S rRNAs, and 22 tRNAs [one-letter code]) are inside the circle. Mutations in mtDNA associated with MELAS and MERRF, and mutations with features of neurodegenerative disorders, such as ataxia, chorea, dystonia, motor neuron disease (MND), and parkinsonism, are boxed.

Besides the fact that it operates under dual genetic control, four other features unique to the behavior of this organelle are important in understanding mitochondrial function in neurodegeneration. First, as opposed to the nucleus, in which there are two sets of chromosomes, there are thousands of mtDNAs in each cell, with approximately five mtDNAs per organelle. Second, organellar division and mtDNA replication operate independently of the cell cycle, both in dividing cells (such as glia) and in postmitotic nondividing cells (such as neurons). Third, upon cell division, the mitochondria (and their mtDNAs) are partitioned randomly between the daughter cells (mitotic segregation). Finally, the number of organelles varies among cells, depending in large part on the metabolic requirements of that cell. Thus, skin fibroblasts contain a few hundred mitochondria, whereas neurons may contain thousands and cardiomyocytes tens of thousands of organelles. Taken together, these features highlight the fact that mitochondria obey the laws of population genetics, not mendelian genetics.

Mitochondria and their DNA are inherited exclusively from the mother. Thus, pathogenic mutations in mtDNA can cause maternally inherited syndromes. Since these mutations arise initially in only one mtDNA, the population of mtDNAs that was originally homoplasmic (i.e., only one mtDNA genotype) becomes heteroplasmic (two or more coexisting mtDNA genotypes). Obviously, the ratio of normal to mutated mtDNAs in a heteroplasmic population, and their spatial and temporal distributions, will be critical in determining whether and when a subpopulation of mutant mtDNAs will have overt phenotypic consequences. In this regard, it is important to note that most mitochondrial diseases due to maternally inherited mutations in mtDNA are recessive, that is, a very high amount of mutated mtDNA must be present (typically more than 70% of the total population of mtDNAs) in order to cause overt dysfunction. Since mtDNA encodes subunits of the respiratory complexes, pathogenic mutations in mtDNA cause diseases arising from problems in OXPHOS. On the other hand, mutations in nucleus-encoded proteins that are targeted to mitochondria, or that affect organellar function indirectly, can affect almost any aspect of cellular function, not just oxidative energy metabolism (see Fig. 2).

Neurodegenerative diseases associated with mutations in mitochondrial genes

Diseases associated with mtDNA mutations are typically heterogeneous and are often multisystemic. Since heart, skeletal muscle, and brain are among the most energy-dependent tissues of the body, it is not surprising that many mitochondrial disorders are encephalocardiomyopathies. The examples of mytochondrial diseases are myoclonus epilepsy with ragged-red fibers (MERRF), Kearns-Sayre syndrome (KSS), progressive external ophthalmoplegia (PEO), Leber hereditary optic neuropathy (LHON), neuropathy, ataxia, and retinitis pigmentosa (NARP), and Leigh syndrome (maternally inherited Leigh syndrome [MILS]).

Neurodegenerative diseases associated with mutations in nuclear gene products that are targeted to mitochondria

Leigh syndrome
Leigh syndrome is a fatal neurodegenerative condition pathologically characterized by subacute symmetrical necrotic lesions in the subcortical regions of the CNS, including thalamus, basal ganglia, brainstem, and spinal cord, accompanied by demyelination, gliosis, and vascular proliferation in affected areas. Onset is most frequently in infancy or early childhood but may sometimes be in adult life. Symptoms include motor and mental regression, dystonia, ataxia, and abnormal breathing. Death generally occurs within 2 years after onset. It is now clear that LS results from impaired mitochondrial energy metabolism, which can arise from a variety of causes. CCO (cytochrome c oxidase) deficiency is one of the most common causes of autosomal-recessive LS.


Fig. 2. Schematic representation of the mitochondrion with its electron transport chain (ETC). The ETC is the principal source of ROS in the cell. In addition to mutations in mtDNA- and nDNA-encoded components of the ETC, a number of mutant mitochondrial proteins that do not belong to the ETC have been associated with neurodegenerative disorders. The intramitochondrial localization and the clinical phenotypes associated with mutations of some of these proteins (in ovals) are indicated.

Friedreich ataxia
Friedreich ataxia (FRDA) is the most common of the hereditary ataxias. It is defined clinically by progressive limb and gait ataxia, axonal sensory neuropathy, absent tendon reflexes, and pyramidal signs. FRDA, which is autosomal-recessive, results from mutations in FRDA, which encodes frataxin, a mitochondrially targeted iron-storage protein. While the pathogenesis of FRDA is still unclear, one possibility is that the presence of unbound (free) reactive iron, via the Fenton reaction, generates free radicals within the mitochondria, leading to oxidative damage and inactivation of mitochondrial enzymes. For unknown reasons, mitochondrial superoxide dismutase (Mn-SOD), a key antioxidant protein, is deficient in cultured cells from FRDA patients, making them even more prone to oxidative damage. The role of oxidative damage in the pathogenesis of FRDA is also supported by the finding that idebenone, an antioxidant similar to ubiquinone, can reduce myocardial hypertrophy and also decrease markers of oxidative stress in FRDA patients.

Hereditary spastic paraplegia
Hereditary spastic paraplegia is a progressive disorder resulting in paraparesis, with onset in childhood or early adulthood. Upper motor neurons are involved selectively, and ataxia and retinitis pigmentosa are also common. Patients with a recessive form of hereditary spastic paraplegia harbor mutations in SPG7, which encodes paraplegin, a mitochondrially targeted protein.

Deafness-dystonia syndrome
Deafness-dystonia syndrome, also called Mohr-Tranebjaerg syndrome, is an X-linked recessive disorder characterized by progressive sensorineural deafness, dystonia, cortical blindness, and psychiatric illness. It results from mutations in TIMM8A, which encodes deafness/dystonia protein-1 (DDP1), a component of the mitochondrial protein import machinery.

Wilson disease
Wilson disease is an early-onset autosomal-recessive disease characterized by movement disorders (e.g., parkinsonism and dystonia), psychiatric symptoms, and liver failure. The defect results from mutations in ATP7B, which encodes a copper-transporting P-type ATPase and results in copper accumulation in kidney, liver, and the basal ganglia of the brain. In fact, mitochondria in affected tissues have morphological abnormalities, as well as deficiency of liver mitochondrial enzymes, especially complex I and aconitase. Thus, oxidative damage mediated by mitochondrial copper accumulation may play a role in the pathogenesis of Wilson disease.

Mitochondrial dysfunctions are also observed in disorders associated with mutations in nonmitochondrial proteins, and in neurodegenerative disorders, such as Alzheimer disease, amyotrophic lateral sclerosis, Huntington disease, Parkinson disease, and progressive supranuclear palsy.

Cell death in mitochondrial and in neurodegenerative disease

Among the numerous stresses known to participate in mitochondrion-mediated apoptosis (Fig. 3), at least in vitro, bioenergetic failure and elevated ROS figure prominently. Thus, two key hypotheses immediately present themselves. First, one would expect a causal relationship between mitochondrial dysfunction and neurodegeneration via apoptosis, perhaps due, at least in part, to changes in ROS levels. Second, if neurodegeneration is related in any way to defects in respiratory chain function or in OXPHOS, then one would expect authentic mitochondrial diseases to show many, if not all, of the features of cell death that are postulated to occur in neurodegenerative diseases. So what do we know about apoptosis and ROS in mitochondrial disease and in neurodegeneration?


Fig. 3. A schematic view of the main pathways of apoptosis: mitochondrion-mediated and mitochondrion-independent.

It is well known that muscle biopsies from patients with "classic" mitochondrial disorders, show little or no evidence of necrosis, fiber loss, elevated circulating creatine kinase, or inflammation. Nevertheless, markers of increased ROS have been found in muscle biopsies from patients with mitochondrial disease. It is clear that elevated ROS are injurious to mitochondria. If markers of elevated ROS and apoptosis can be found in these muscle biopsies, why do these muscle fibers not degenerate? This apparent paradox points out that a marker of apoptosis is merely that ‐ a marker ‐ and does not necessarily imply that apoptosis is actually occurring. In skeletal muscle, there are at least two well-characterized reasons why apoptosis is not occurring in muscle. What about neuronal death in mitochondrial disease? There is neuronal loss in KSS, MERRF, and MELAS, and the regions that are affected differ in each disease, but no studies have been published regarding apoptosis in these cells. Therefore, it is still unclear how neurons die in mitochondrial disorders.

It is clear that impairment of mitochondrial energy metabolism is the key pathogenic factor in a number of neurodegenerative disorders This is most clearly seen in maternally inherited diseases that result from pathogenic mutations in mtDNA that interdict the normal functioning of the respiratory chain and OXPHOS. Examples of this group of diseases include LHON and maternally inherited LS. Similarly, mutations in nuclear genes that encode mitochondrially targeted proteins required for respiratory chain assembly and homeostasis can cause neurodegenerative disease. Examples in this class are autosomal-recessive LS, FRDA, hereditary spastic paraplegia, and Mohr-Tranebjaerg syndrome.

What is striking about both of these groups of neurodegenerative disorders is how diverse they are in their clinical manifestations, and how little they resemble the "classic" neurodegenerative disorders ‐ AD, ALS, HD, PD, and PSP ‐ that have no obvious connection to primary mitochondrial bioenergetic dysfunction. It is remarkable that almost no pathogenic mutation in mtDNA causes the typical clinical manifestations associated with the most common neurodegenerative diseases. This does not mean, however, that OXPHOS defects play no role in the late-onset neurodegenerative diseases. Rather, mitochondrial dysfunction probably plays an important, but secondary, role in these disorders. For example, it is clear that there is respiratory chain deficiency in hippocampal neurons in AD patients, as measured by biochemistry, histochemistry, and immunohistochemistry. It is likely, however, that these deficits are secondary to some underlying dysfunction, of which Aβ deposition is but one of many possible primary causes.

Source: Eric A. Schon and Giovanni Manfredi. Neuronal degeneration and mitochondrial dysfunction. J. Clin. Invest. 111:303-312 (2003).
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