title: A reversible component of mitochondrial respiratory dysfunction in apoptosis can be rescued by exogenous cytochrome c.
abstract: Multiple apoptotic pathways release cytochrome c from the mitochondrial intermembrane space, resulting in the activation of downstream caspases. In vivo activation of Fas (CD95) resulted in increased permeability of the mitochondrial outer membrane and depletion of cytochrome c stores. Serial measurements of oxygen consumption, NADH redox state and membrane potential revealed a loss of respiratory state transitions. This tBID-induced respiratory failure did not require any caspase activity. At early time points, re-addition of exogenous cytochrome c markedly restored respiratory functions. Over time, however, mitochondria showed increasing irreversible respiratory dysfunction as well as diminished calcium buffering. Electron microscopy and tomographic reconstruction revealed asymmetric mitochondria with blebs of herniated matrix, distended inner membrane and partial loss of cristae structure. Thus, apoptogenic redistribution of cytochrome c is responsible for a distinct program of mitochondrial respiratory dysfunction, in addition to the activation of downstream caspases.
authors.affiliation: Howard Hughes Medical Institute, Department of Pathology, Harvard Medical School, Dana Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: V K
authors.initials: VK
authors.lastname: Mootha
authors.forename: M C
authors.initials: MC
authors.lastname: Wei
authors.forename: K F
authors.initials: KF
authors.lastname: Buttle
authors.forename: L
authors.initials: L
authors.lastname: Scorrano
authors.forename: V
authors.initials: V
authors.lastname: Panoutsakopoulou
authors.forename: C A
authors.initials: CA
authors.lastname: Mannella
authors.forename: S J
authors.initials: SJ
authors.lastname: Korsmeyer
mesh_terms: D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D003574:Cytochrome c Group / Q000494:pharmacology*; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D015398:Signal Transduction; D019014:fas Receptor / Q000378:metabolism
chemical_list: D003574:Cytochrome c Group; D019014:fas Receptor; D002118:Calcium