Cytochrome C Maintains Mitochondrial Transmembrane Potential and Atp Generation after Outer Mitochondrial Membrane Permeabilization during the Apoptotic Process

TLDR

During apoptosis, cytochrome c release from permeabilized mitochondria triggers caspase activation, yet its effect on mitochondrial metabolism remains unclear. Mitochondria maintain transmembrane potential and ATP production by utilizing cytoplasmic cytochrome c after outer membrane permeabilization. When caspase activity is inhibited, mitochondrial depolarization following outer membrane permeabilization recovers within 30–60 min and is sustained; cytochrome c release and apoptosis proceed normally even when mitochondria are uncoupled, indicating that cytochrome c release does not compromise inner membrane integrity and that mitochondrial functions can persist without caspase activation.

Abstract

During apoptosis, cytochrome c is released into the cytosol as the outer membrane of mitochondria becomes permeable, and this acts to trigger caspase activation. The consequences of this release for mitochondrial metabolism are unclear. Using single-cell analysis, we found that when caspase activity is inhibited, mitochondrial outer membrane permeabilization causes a rapid depolarization of mitochondrial transmembrane potential, which recovers to original levels over the next 30–60 min and is then maintained. After outer membrane permeabilization, mitochondria can use cytoplasmic cytochrome c to maintain mitochondrial transmembrane potential and ATP production. Furthermore, both cytochrome c release and apoptosis proceed normally in cells in which mitochondria have been uncoupled. These studies demonstrate that cytochrome c release does not affect the integrity of the mitochondrial inner membrane and that, in the absence of caspase activation, mitochondrial functions can be maintained after the release of cytochrome c.