Resistance to Caspase-Independent Cell Death Requires Persistence of Intact Mitochondria

SummaryDuring apoptosis, mitochondrial outer membrane permeabilization (MOMP) is often a point-of-no-return; death can proceed even if caspase activation is disrupted. However, under certain conditions, resistance to MOMP-dependent, caspase-independent cell death is observed. Mitochondrial recovery represents a key process in this survival. Live cell imaging revealed that during apoptosis not all mitochondria in a cell necessarily undergo MOMP. This incomplete MOMP (iMOMP) was observed in response to various stimuli and in different cell types regardless of caspase activity. Importantly, the presence of intact mitochondria correlated with cellular recovery following MOMP, provided that caspase activity was blocked. Such intact mitochondria underwent MOMP in response to treatment of cells with the Bcl-2 antagonist ABT-737, suggesting that the resistance of these mitochondria to MOMP lies at the point of Bax or Bak activation. Thus, iMOMP provides a critical source of intact mitochondria that permits cellular survival following MOMP.

Graphical AbstractFigure optionsDownload high-quality image (246 K)Download as PowerPoint slideHighlights
► Apoptotic mitochondrial outer membrane permeabilization (MOMP) can be incomplete
► Caspase-inhibited cell survival following MOMP requires intact mitochondria
► Intact mitochondria are dynamic and can repopulate the cell
► Bcl-2 antagonists promote complete MOMP and inhibit cell survival