The tumour suppressor LACTB remodels mitochondria to promote cytochrome c release and apoptosis

Mitochondria are pivotal regulators of cellular homeostasis, integrating energy metabolism, biosynthesis, and programmed cell death (apoptosis). During apoptosis, mitochondrial outer membrane permeabilization by BAX/BAK pores facilitates release of apoptotic factors, while the role of inner mitochondrial membrane (IMM) remodelling remains less understood. Here, we identify LACTB, a filament-forming serine protease and tumour suppressor, as a regulator of IMM dynamics during apoptosis. LACTB is required for apoptosis-induced IMM remodelling, which in turn causes increased release of cytochrome c and other mitochondrial apoptotic factors. LACTB-induced membrane remodelling is independent of OPA1 processing. Rather, purified LACTB binds and remodels cardiolipin-enriched membrane nanotubes preferentially over planar lipid membranes, suggesting a direct effect in apoptotic membrane remodelling. Intriguingly, LACTB is not required for mitochondrial shape changes induced by mitochondrial depolarization, suggesting that LACTB action is apoptosis-specific. Collectively, our findings establish LACTB as a mediator of apoptosis-induced IMM remodelling, suggesting a mechanism for tumour suppression in cancer.