Mitochondria1 involvement in Parkinson's disease

The role of mitochondrial dysfunction in the pathogenesis of Parkinson’s disease (PD) has generated a flurry of original articles, reviews, and editorials in recent years, a sure sign that the subject is still open to controversy. There are, actually, two major controversies on the subject, one dealing with biochemistry, the other with molecular genetics. The biochemical controversy centers on whether defects of the respiratory chain, and especially of complex I, are present in tissues from PD patients. The second controversy regards the possible pathogenic role of mutations in mitochondria1 DNA (mtDNA). Two papers in this issue of Neurology exemplif y the debate. Similar biochemical studies in muscle biopsies of PD patients from geographically related countries (Italy and Spain) gave very different results: DiDonato et all found no difference in the activities of respiratory chain complexes in pat ients a n d age-matched controls, whereas Cardellach et a12 found decreased activities not only of complex I but also, and even more markedly, of complex IV (cytochrome c oxidase; COX). Regrettably, in the latter work, histochemical studies did not include a stain for COX, which might have revealed whether COX deficiency involved all fibers (as occurs in defects of the nuclear genome) or affected individual fibers, as is typical in defects of mtDNA.3 This is only the latest act in a long-standing controversy over biochemical data in PD, and contradictory results were obtained in all three tissues studied: brain, muscle, and platelets (table 1). Of the five complexes of the respiratory chain, complex I (NADH-coenzyme Q reductase) has received the greatest attention for at least two reasons: (1) two different groups reported a specific defect of complex I in the substantia nigra4,5 and in platelets6 of PD patients, and (2) the active metabolite of l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine, a neurotoxin that induces parkinsonism in humans and primates, is a specific inhibitor of complex 1.7 The most consistent and convincing evidence of complex I deficiency in PD comes from studies of brain tissue. Although these s tud ie~~>~J ,* were conducted by a single group and need to be repeated by others, great care was taken in considering all variables that might cause a spurious or secondary defect of complex I, such as age, medication, agonal period, brain pathology, and time between death and autopsy. The specificity of the enzyme defect and its selectivity for the substantia nigra support a pathogenic role. The partial nature of the defect, however, suggests that it might act in conjunction with other genetic or environmental factors. Attempts at defining which subunits of complex I were defective (at latest count, complex I is composed of about 40 subunits, seven of which are encoded by mtDNA and the others by nuclear DNA) have given controversial results: the Western blot pattern was normal in one study,5 but in another it suggested a selective decrease of lower molecular-weight subunit^. ^ Employing these antibodies in immunohistochemical studies of the substantia nigra might help confirm and localize the enzyme defect at the single-cell level.1° In muscle, biochemical studies have been either normal o r consistent with multiple respiratory chain defects (table 1). Partial defects of complexes containing mtDNA-encoded subunits, such as complexes I, 111, and IV, often occur in disorders associated with mtDNA deletions or with point mutations in tRNA genes of mtDNA.3 In PD, these findings have suggested that mutations of mtDNA may play a role in the pathogenesis of the disease, which leads us to the “molecular genetic controversy. ” The high rate of spontaneous mutation and the poor repair capacity of mtDNA lead to a gradual accumulation of mutations, especially in postmitotic tissue, such as heart, muscle, and brain, a phenomenon that may well explain some of the degen-