Lack of apoptosis in mitochondrial encephalomyopathies

Background/Objective: Apoptosis: or programmed cell death, is an evolutiona ry conserved mechanism essential for morphogenesis and tissue homeostasis, but it plays an important role also in pathologic conditions, including neu rologic disorders. Its execution pathway is critically regulated at the mit ochondrial level. Evidence of apoptosis in muscle specimens was investigate d in patients with genetically defined mitochondrial encephalomyopathies. M ethods: Thirty-three muscle biopsies from patients with genotypically diffe rent mitochondrial diseases (single and multiple deletions, A3243G/A8344G p oint mutations of the mitochondrial DNA) were studied. The terminal deoxynu cleotidyl transferase-mediated dUTP nick end labeling (TUNEL) reaction was used as a marker of nuclear DNA fragmentation? as well as antibodies agains t pro- (Fas) or anti- (Bcl-2) apoptotic factors. Also, because one hallmark of apoptosis is morphologic, ultrastructural studies were performed on ske letal muscle from 18 of 33 patients, examining both phenotypically normal a nd ragged red fibers. Results: In all muscle biopsies, no significant expre ssion of either pro (Fas) and inhibiting (Bcl-2) apoptosis-related proteins was found, nor TUNEL, positivity. This latter finding is confirmed by lack of morphologic evidence of apoptosis in all the fibers examined at the ult rastructural level. Conclusion: The authors' findings suggest that genetica lly determined defects of oxidative phosphorylation do not induce the apopt otic process and that apoptosis is not involved in the pathogenesis of mito chondrial disorders.