The mitochondrial respiratory chain is a modulator of apoptosis.
Mitochondrial dysfunction and dysregulation of apoptosis are implicated in many diseases such as cancer and neurodegeneration. We investigate here the role of respiratory chain (RC) dysfunction in apoptosis, using mitochondrial DNA mutations as genetic models. Although some mutations eliminate the entire RC, others target specific complexes, resulting in either decreased or complete loss of electron flux, which leads to impaired respiration and adenosine triphosphate (ATP) synthesis. Despite these similarities, significant differences in responses to apoptotic stimuli emerge. Cells lacking RC are protected against both mitochondrial- and endoplasmic reticulum (ER) stress-induced apoptosis. Cells with RC, but unable to generate electron flux, are protected against mitochondrial apoptosis, although they have increased sensitivity to ER stress. Finally, cells with a partial reduction in electron flux have increased apoptosis under both conditions. Our results show that the RC modulates apoptosis in a context-dependent manner independent of ATP production and that apoptotic responses are the result of the interplay between mitochondrial functional state and environmental cues.
Kwong
Jennifer Q
JQ
Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY 10021, USA.
Henning
Matthew S
MS
Starkov
Anatoly A
AA
Manfredi
Giovanni
G
D000255:Adenosine Triphosphate / Q000096:biosynthesis; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D004272:DNA, Mitochondrial / Q000737:chemistry; D004579:Electron Transport / Q000235:genetics / Q000502:physiology*; D042967:Electron Transport Complex I / Q000235:genetics; D042963:Electron Transport Complex II / Q000235:genetics; D014450:Electron Transport Complex III / Q000235:genetics; D003576:Electron Transport Complex IV / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism; D009154:Mutation; D017382:Reactive Oxygen Species / Q000378:metabolism; D019311:Staurosporine / Q000494:pharmacology
D004272:DNA, Mitochondrial; D004791:Enzyme Inhibitors; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; D042963:Electron Transport Complex II; D003576:Electron Transport Complex IV; D042967:Electron Transport Complex I; D014450:Electron Transport Complex III; D019311:Staurosporine; D002118:Calcium