Programmed cell death is physiological when disposing of senescent, dysfunctional, or redundant cells, but pathological if these cells cannot be replaced. Mitochondria help determine cell fate as "gatekeepers" of apoptosis and effectors of cell necrosis. Apoptosis was first described 40 years ago this year. Cell suicide (or the less emotionally charged "programmed cell death") impacts organism development, normal organ homeostasis, and degenerative (too much cell death) or metaplastic (too little cell death) diseases. The components of apoptosis signaling through mitochondrial targeted Bcl-2 family proteins and activation of the caspase cascade and its downstream proteases and nucleases are well described. More recently, we have realized that there is a parallel cell death pathway, programmed necrosis, in which calcium cross-talk between endoplasmic reticulum and mitochondria causes mitochondrial depolarization, reversal of electron flow through the electron transport chain, and ATP depletion. Since apoptosis and programmed necrosis signaling can occur concurrently in a suicidal cell and are difficult to distinguish using conventional techniques, their relative roles in disease are still being researched and debated. Here, the different molecular mechanisms, effects, and pathophysiological implications of apoptosis and programmed necrosis are reviewed as they relate to heart failure and diabetes mediated by the Bcl-2 family protein, Nix.
- mitochondrial permeability transition pore