Cytochrome c release from rat brain mitochondria is proportional to the mitochondrial functional deficit: implications for apoptosis and neurodegenerative disease.
Apoptosis may be initiated in neurons via mitochondrial release of the respiratory protein, cytochrome c. The mechanism of cytochrome c release has been studied extensively, but little is known about its dynamics. It has been claimed that release is all-or-none, however, this is not consistent with accumulating evidence of cytosolic mechanisms for 'buffering' cytochrome c. This study has attempted to model an underlying disease pathology, rather than inducing apoptosis directly. The model adopted was diminished activity of the mitochondrial respiratory chain complex I, a recognized feature of Parkinson's disease. Titration of rat brain mitochondrial respiratory function, with the specific complex I inhibitor rotenone, caused proportional release of cytochrome c from isolated synaptic and non-synaptic mitochondria. The mechanism of release was mediated, at least in part, by the mitochondrial outer membrane component Bak and voltage-dependent anion channel rather than non-specific membrane rupture. Furthermore, preliminary data were obtained demonstrating that in primary cortical neurons, titration with rotenone induced cytochrome c release that was subthreshold for the induction of apoptosis. Implications for the therapy of neurodegenerative diseases are discussed.
Clayton
Rebecca
R
Miriam Marks Division of Neurochemistry, Institute of Neurology, University College London, London, UK.
Clark
John B
JB
Sharpe
Martyn
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001921:Brain / Q000201:enzymology* / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000201:enzymology* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D012402:Rotenone / Q000494:pharmacology
D012402:Rotenone; D045304:Cytochromes c