Autophagy Controls the Kinetics and Extent of Mitochondrial Apoptosis by Regulating PUMA Levels

• Autophagy controls mitochondrial permeabilization (MOMP) timing in apoptosis
• Autophagy promotes inefficient MOMP and can allow cellular recovery
• Autophagy selectively regulates PUMA levels
• PUMA depletion prevents sensitization to apoptosis by autophagy inhibition

SummaryMacroautophagy is thought to protect against apoptosis; however, underlying mechanisms are poorly understood. We examined how autophagy affects canonical death receptor-induced mitochondrial outer membrane permeabilization (MOMP) and apoptosis. MOMP occurs at variable times in a population of cells, and this is delayed by autophagy. Additionally, autophagy leads to inefficient MOMP, after which some cells die through a slower process than typical apoptosis and, surprisingly, can recover and divide afterward. These effects are associated with p62/SQSTM1-dependent selective autophagy causing PUMA levels to be kept low through an indirect mechanism whereby autophagy affects constitutive levels of PUMA mRNA. PUMA depletion is sufficient to prevent the sensitization to apoptosis that occurs when autophagy is blocked. Autophagy can therefore control apoptosis via a key regulator that makes MOMP faster and more efficient, thus ensuring rapid completion of apoptosis. This identifies a molecular mechanism whereby cell-fate decisions can be determined by autophagy.

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