Mitochondrial abnormalities have been implicated in the pathogenesis of many genetic diseases and several degenerative diseases like Parkinson's (50). In most genetic mitochondrial diseases there is a very specific mutation in the mitochondrial or nuclear DNA encoding a specific mitochondrial protein. For example, Leber's hereditary optical neuropathy (LHON), a highly selective degeneration of the optic nerve, presents with acute blindness in mid-life. A specific mutation in the mitochondrial gene (ND6) encoding for a subunit of NADH dehydrogenase has been identified (51). This results in a substantial decrease in the activity of complex I of the ETC. Complex I is a critical part of the mitochondrial ETC and thus of cellular respiration. However, the phenotype of the LHON is surprisingly restricted to the optic nerve.
In Friedrich's ataxia, an autosomal recessive disease that results in cerebellar ataxia, peripheral neuropathy, and hypertrophic cardiomyopathy, the mutant protein, frataxin, is targeted to the mitochondrial inner membrane and functions to transport iron out of the mitochondrion (47). With the loss of this protein, iron accumulates in the mitochondrial matrix, stimulating the conversion of H202 to by the Fenton reaction. This inactivates the mitochondrial Fe-S center enzymes (complexes I, II, III, and aconitase), which in turn reduces mitochondrial energy production (47). The phenotype of this ataxia is restricted to the central nervous system (CNS) and the heart.
These observations suggest the presence of mitochondrial diversity among tissues, where the role or the relative importance of a mitochondrial protein or pathway varies from one tissue to another; disease is expressed only in tissues in which the affected mitochondrial proteins are of critical importance.
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