Apoptosis in mitochondrial encephalomyopathies with mitochondrial DNA mutations: a potential pathogenic mechanism

Mitochondrial encephalomyopathies caused by mitochondrial DNA (mtDNA) defec ts are a genetically and phenotypically heterogeneous group of disorders. T he site, percentage and distribution of mutations do not explain the overal l clinical heterogeneity that is found, Apoptosis (programmed cell death) i s an evolutionarily conserved mechanism that is essential for tissue develo pment and homeostasis, Dysregulation of apoptosis has been implicated in th e pathogenesis of various human diseases, such as cancer and autoimmune and neurodegenerative disorders. Recent in vitro evidence has indicated the ce ntral role of mitochondria in the apoptotic process, We investigated the oc currence of apoptosis in muscle biopsies of 36 patients carrying different mtDNA mutations and four patients with inclusion body myositis and mitochon drial abnormalities. Apoptotic features, mainly localized in cytochrome c o xidase-negative fibres, were observed in muscle fibres of patients carrying a high percentage of single mtDNA deletions (>40 %) and of tRNA point muta tions (>70%), By contrast, no apoptotic changes were observed in inclusion body myositis and in patients carrying mutations of mtDNA structural genes. Our study suggests that apoptosis is not simply a means whereby cells with dysfunctional mitochondria are eliminated, but that it seems to play a rol e in the pathogenesis of mitochondrial disorders associated with mtDNA defe cts affecting mitochondrial protein synthesis. The imbalance and relative a bundances of nuclear-encoded and mtDNA-encoded subunits may favour cytochro me c inactivation and release. Cytochrome c, together with respiratory chai n dysfunction, could activate apoptotic pathways that, in turn, inhibit the rate of mitochondrial translation and the importation of nuclear-encoded m itochondrial protein precursors. This vicious circle may amplify the bioche mical defects and tissue damage and contribute to the modulation of clinica l features.