Mitochondrial outer membrane permeabilization (MOMP) is a core event in apoptosis signaling. However, the underlying mechanism of BAX and BAK pore formation remains incompletely understood. We demonstrate that mitochondria are globally and dynamically targeted by endolysosomes (ELs) during MOMP. In response to pro-apoptotic BH3-only protein signaling and pharmacological MOMP induction, ELs increasingly form transient contacts with mitochondria. Subsequently, ELs rapidly accumulate within the entire mitochondrial compartment. This switch-like accumulation period temporally coincides with mitochondrial BAX clustering and cytochrome c release. Remarkably, interactions of ELs with mitochondria control BAX recruitment and pore formation. Knockdown of Rab5A, Rab5C, or USP15 interferes with EL targeting of mitochondria and functionally uncouples BAX clustering from cytochrome c release, while knockdown of the Rab5 exchange factor Rabex-5 impairs both BAX clustering and cytochrome c release. Together, these data reveal that EL-mitochondrial inter-organelle communication is an integral regulatory component of functional MOMP execution during cellular apoptosis signaling.

线粒体外膜通透性（MOMP）是凋亡信号转导中的核心事件。但是，BAX和BAK孔形成的潜在机制仍不完全了解。我们证明线粒体是全球范围内，并在MOMP期间由溶酶体（ELs）动态靶向。为了响应促凋亡的仅BH3蛋白信号传导和药理MOMP诱导，EL越来越多地与线粒体形成瞬时接触。随后，ELs在整个线粒体区室中迅速积累。这种类似开关的积累期在时间上与线粒体BAX簇和细胞色素c释放。值得注意的是，EL与线粒体的相互作用控制BAX募集和孔形成。敲低Rab5A，Rab5C或USP15会干扰线粒体的EL靶向作用，并使BAX簇与细胞色素c释放功能解除偶联，而敲除Rab5交换因子Rabex-5会损害BAX簇和细胞色素c释放。这些数据在一起表明，EL-线粒体细胞器间通讯是细胞凋亡信号传导过程中功能性MOMP执行的不可或缺的调节成分。