W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205, USA; Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205, USA.
Dev Cell. 2020 Jun 22;53(6):627-645.e7. doi: 10.1016/j.devcel.2020.05.014. Epub 2020 Jun 5.
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）是细胞凋亡信号转导的核心事件。然而，BAX 和 BAK 孔形成的潜在机制仍不完全清楚。我们证明，在 MOMP 过程中，线粒体被内溶酶体（ELs）整体和动态靶向。在响应促凋亡 BH3 仅蛋白信号和药物诱导的 MOMP 时，ELs 与线粒体之间形成短暂接触的频率增加。随后，ELs 在整个线粒体区室中快速积累。这种开关样积累期与线粒体 BAX 聚集和细胞色素 c 释放的时间完全吻合。值得注意的是，ELs 与线粒体的相互作用控制 BAX 的募集和孔形成。Rab5A、Rab5C 或 USP15 的敲低干扰了 EL 对线粒体的靶向，并且功能性地将 BAX 聚集与细胞色素 c 释放解偶联，而 Rab5 交换因子 Rabex-5 的敲低则同时损害 BAX 聚集和细胞色素 c 释放。总之，这些数据表明，EL-线粒体细胞器间通讯是细胞凋亡信号转导过程中功能性 MOMP 执行的一个完整的调节组成部分。
