A reversible component of mitochondrial respiratory dysfunction in apoptosis can be rescued by exogenous cytochrome c

Multiple apoptotic pathways release cytochrome c from the mitochondrial int ermembrane space, resulting in the activation of downstream caspases. In vi vo activation of Fas (CD95) resulted in increased permeability of the mitoc hondrial outer membrane and depletion of cytochrome c stores. Serial measur ements of oxygen consumption, NADH redox state and membrane potential revea led a loss of respiratory state transitions, This tBID-induced respiratory failure did not require any caspase activity. At early time points, re-addi tion of exogenous cytochrome c markedly restored respiratory functions. Ove r time, however, mitochondria showed increasing irreversible respiratory dy sfunction as well as diminished calcium buffering. Electron microscopy and tomographic reconstruction revealed asymmetric mitochondria with blebs of h erniated matrix, distended inner membrane and partial loss of cristae struc ture. Thus, apoptogenic redistribution of cytochrome c is responsible for a distinct program of mitochondrial respiratory dysfunction, in addition to the activation of downstream caspases.