Lack of apoptosis in mitochondrial encephalomyopathies.
OBJECTIVE
Apoptosis, or programmed cell death, is an evolutionary conserved mechanism essential for morphogenesis and tissue homeostasis, but it plays an important role also in pathologic conditions, including neurologic disorders. Its execution pathway is critically regulated at the mitochondrial level. Evidence of apoptosis in muscle specimens was investigated in patients with genetically defined mitochondrial encephalomyopathies.


METHODS
Thirty-three muscle biopsies from patients with genotypically different mitochondrial diseases (single and multiple deletions, A3243G/A8344G point mutations of the mitochondrial DNA) were studied. The terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) reaction was used as a marker of nuclear DNA fragmentation, as well as antibodies against pro- (Fas) or anti- (Bcl-2) apoptotic factors. Also, because one hallmark of apoptosis is morphologic, ultrastructural studies were performed on skeletal muscle from 18 of 33 patients, examining both phenotypically normal and ragged red fibers.


RESULTS
In all muscle biopsies, no significant expression 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 ultrastructural level.


CONCLUSIONS
The authors' findings suggest that genetically determined defects of oxidative phosphorylation do not induce the apoptotic process and that apoptosis is not involved in the pathogenesis of mitochondrial disorders.
Sciacco
M
M
Centro Dino Ferrari, Istituto di Clinica Neurologica, University of Milan, Ospedale Maggiore IRCCS, Milan, Italy.
Fagiolari
G
G
Lamperti
C
C
Messina
S
S
Bazzi
P
P
Napoli
L
L
Chiveri
L
L
Prelle
A
A
Comi
G P
GP
Bresolin
N
N
Scarlato
G
G
Moggio
M
M
D017209:Apoptosis / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D002352:Carrier Proteins / Q000378:metabolism; D053938:DNA Fragmentation / Q000502:physiology*; D004272:DNA, Mitochondrial / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins; D017237:Mitochondrial Encephalomyopathies / Q000235:genetics / Q000378:metabolism*; D018656:Muscle Fibers, Fast-Twitch / Q000378:metabolism* / Q000648:ultrastructure; D009154:Mutation / Q000235:genetics / Q000502:physiology*; D009842:Oligopeptides / Q000378:metabolism; D011518:Proto-Oncogene Proteins
D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D002352:Carrier Proteins; D004272:DNA, Mitochondrial; D008565:Membrane Proteins; D009842:Oligopeptides; D011518:Proto-Oncogene Proteins; C096131:valyl-glutamyl-isoleucyl-asparaginyl-cysteinyl-threonyl-arginine