Endolysosomal Targeting of Mitochondria Is Integral to BAX-Mediated Mitochondrial Permeabilization during Apoptosis Signaling
Endolysosomal Targeting of Mitochondria Is Integral to BAX-Mediated Mitochondrial Permeabilization during Apoptosis Signaling
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DOI：
10.1016/j.devcel.2020.05.014
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发表时间：
2020-06-22
影响因子：
11.8
通讯作者：
Hamacher-Brady, Anne
中科院分区：
文献类型：
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作者：
Wang, Tim Sen;Coppens, Isabelle;Hamacher-Brady, Anne
线粒体外膜透化（MOMP）是细胞凋亡信号转导的核心事件。然而，BAX和巴克孔形成的潜在机制仍然不完全清楚。我们证明，线粒体是全球性的和动态的目标内溶酶体（ELs）在MOMP。响应于促凋亡的仅BH 3蛋白信号传导和药理学MOMP诱导，EL越来越多地与线粒体形成瞬时接触。随后，EL在整个线粒体区室中迅速积累。这种开关样积累期与线粒体BAX聚类和细胞色素c释放在时间上一致。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，Rab 5A、Rab 5C或USP 15的敲低干扰线粒体的EL靶向，并在功能上使BAX聚集与细胞色素c释放解偶联，而Rab 5交换因子Rabex-5的敲低损害BAX聚集和细胞色素c释放。总之，这些数据表明，EL-线粒体细胞器间通信是细胞凋亡信号传导过程中功能性MOMP执行的一个不可或缺的调节组分。
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.