Calcium influx through T-type calcium channels regulates secondary necrosis and inflammation through recruitment of ATG9A-mediated membrane repair

Approximately 200–300 billion cells die daily through apoptosis, a prominent form of programmed cell death, to maintain tissue homoeostasis. If apoptotic cells are not efficiently removed by phagocytes, they progress to secondary necrosis when the plasma membrane (PM) becomes permeabilised and release proinflammatory damage-associated molecular patterns (DAMPs) such as HMGB1 and ATP, which drive inflammation and contribute to autoimmune diseases. Thus, controlling inflammation through maintaining PM integrity is critical, however the molecular mechanisms underpinning this is not well defined. Here, we reveal a calcium-dependent process that delays secondary necrosis by promoting PM repair. Mechanistically, calcium influx through T-type voltage-gated calcium channels mediates the recruitment of the lipid scramblase ATG9A and Golgi components to damaged PM regions, thereby preventing early cellular lysis and DAMP release. Inhibition of calcium influx or loss of ATG9A accelerates PM rupture, increases DAMP secretion, and exacerbates inflammatory cell recruitment in vivo. Taken together, this study establishes a novel role for T-type calcium channels and ATG9A in regulating PM repair during apoptosis and highlights their therapeutic potential for controlling unwanted inflammation.