The tumor 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 BCL-2-associated X protein/BCL-2 Homolog Antagonist Killer (BAX/BAK) pores facilitates release of apoptotic factors, while the role of inner mitochondrial membrane (IMM) remodeling remains less understood. Here, we identify serine beta-lactamase-like protein (LACTB), a filament-forming serine protease and tumor suppressor, as a regulator of IMM dynamics during apoptosis. LACTB suppression reduces cytochrome c release and apoptosis, whereas its overexpression promotes these effects. LACTB does not affect BAX or Drp1 recruitment to mitochondria. Rather, LACTB is required for apoptosis-induced mitochondrial remodeling, independent of OPA1 processing. Intriguingly, LACTB knockdown does not affect mitochondrial shape changes induced by CCCP treatment, suggesting that LACTB action is apoptosis-specific. Purified LACTB binds and remodels cardiolipin-enriched membrane nanotubes preferentially over planar lipid membranes, suggesting a direct effect in apoptotic membrane remodeling. Collectively, our findings suggest LACTB to be a mediator of apoptosis-induced IMM remodeling, a possible mechanism for tumor suppression in cancer.