A mitochondrial FUNDC1/HSC70 interaction organizes the proteostatic stress response at the risk of cell morbidity
A mitochondrial FUNDC1/HSC70 interaction organizes the proteostatic stress response at the risk of cell morbidity
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DOI：
10.15252/embj.201798786
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发表时间：
2019-02-01
期刊：
影响因子：
11.4
通讯作者：
Chen, Quan
中科院分区：
文献类型：
--
作者：
Li, Yanjun;Xue, Yanhong;Chen, Quan
蛋白质质量和线粒体质量对于细胞活性都是至关重要的，蛋白质稳态受损和线粒体功能障碍是衰老和年龄相关疾病的常见病因。在这里，我们报告，线粒体外膜蛋白FUNDC 1与伴侣HSC 70相互作用，以促进未折叠的胞浆蛋白的线粒体易位，通过LONP 1降解或在培养的人细胞中蛋白酶体抑制后形成非侵袭性的细胞外基质相关蛋白聚集体（MAPA）。包括csCLEM、Apex和生化分析的综合方法揭示MAPAs含有泛素化的胞质蛋白、自噬受体p62和线粒体蛋白。MAPA以FIS 1依赖性方式与线粒体分离，随后可通过自噬降解。尽管FUNDC 1/HSC 70途径促进未折叠胞质蛋白的降解，但在MAPA形成之前线粒体上未折叠蛋白的过度积累损害线粒体完整性并激活AMPK，导致细胞衰老。我们认为，人类线粒体组织细胞蛋白质稳态反应的风险，他们自己的故障和细胞的杀伤力。
Both protein quality and mitochondrial quality are vital for the cellular activity, and impaired proteostasis and mitochondrial dysfunction are common etiologies of aging and age-related disorders. Here, we report that the mitochondrial outer membrane protein FUNDC1 interacts with the chaperone HSC70 to promote the mitochondrial translocation of unfolded cytosolic proteins for degradation by LONP1 or for formation of non-aggresomal mitochondrion-associated protein aggregates (MAPAs) upon proteasome inhibition in cultured human cells. Integrative approaches including csCLEM, Apex, and biochemical analysis reveal that MAPAs contain ubiquitinated cytosolic proteins, autophagy receptor p62, and mitochondrial proteins. MAPAs are segregated from mitochondria in a FIS1-dependent manner and can subsequently be degraded via autophagy. Although the FUNDC1/HSC70 pathway promotes the degradation of unfolded cytosolic proteins, excessive accumulation of unfolded proteins on the mitochondria prior to MAPA formation impairs mitochondrial integrity and activates AMPK, leading to cellular senescence. We suggest that human mitochondria organize cellular proteostatic response at the risk of their own malfunction and cell lethality.