Apoptosis and non-inflammatory phagocytosis can be induced by mitochondrial damage without caspases

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Abstract
A central issue regarding vertebrate apoptosis is whether caspase activity is essential, particularly for its crucial biological outcome: non-inflammatory clearance of the dying cell. Caspase-9 is required for the proteolytic cascade unleashed by the mitochondrial outer membrane permeabilization (MOMP) regulated by the Bcl-2 protein family. However, despite the severely blunted apoptosis in cells from Casp9−/− mice, some organs with copious apoptosis, such as the thymus, appear unaffected. To address this paradox, we investigated how caspase-9 loss affects apoptosis and clearance of mouse fibroblasts and thymocytes. Although Casp9−/− cells were initially refractory to apoptotic insults, they eventually succumbed to slower caspase-independent cell death. Furthermore, in γ-irradiated mice, the dying Casp9−/− thymocytes were efficiently cleared, without apparent inflammation. Notably, MOMP proceeded normally, and the impaired mitochondrial function, revealed by diminished mitochondrial membrane potential (ΔΨm), committed cells to die, as judged by loss of clonogenicity. Upon the eventual full collapse of ΔΨm, presumably reflecting failure of respiration, intact dying Casp9−/− cells unexpectedly exposed the prototypic ‘eat-me’ signal phosphatidylserine, which allowed their recognition and engulfment by phagocytes without overt inflammation. Hence, caspase-9-induced proteolysis accelerates apoptosis, but impaired mitochondrial integrity apparently triggers a default caspase-independent program of cell death and non-inflammatory clearance. Thus, caspases appear dispensable for some essential biological functions of apoptosis.