FUNDC1 regulates mitochondrial dynamics at the ER-mitochondrial contact site under hypoxic conditions

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作   者：

Wu, Wenxian;  Lin, Chunxia;  Wu, Keng;  Jiang, Lei;  Wang, Xiaojing;  Li, Wen;  Zhuang, Haixia;  Zhang, Xingliang;  Chen, Hao;  Li, Shupeng;  Yang, Yue;  Lu, Yue;  Wang, Jingjing;  Zhu, Runzhi;  Zhang, Liangqing;  Sui, Senfang;  Tan, Ning;  Zhao, Bin;  Zhang, Jingjing;  Li, Longxuan;  Feng, Du; 

作者机构：

Dept Neurol;  Dept Anesthesiol;  Shanghai;  Dept Cardiovasol;  Affiliated Hosp;  Peoples R China;  Guangdong Acad Med Sci;  Beijing;  Guangdong;  Zhanjiang;  Guangdong Key Lab Age Related Cardiac Cerebral Va;  Guangdong Med Univ;  Guangdong Gen Hosp;  Zhanjiang Key Lab Hepatobiliary Dis;  State Key Lab Biomembrane & Membrane Biotechnol;  Peoples R;  Southern Med Univ;  Gongli Hosp;  Tsinghua Univ;  Pudong New Area;  Guangzhou;  Lab Hepatobiliary Surg;  Dept Pediat;  Sch Life Sci; 

关键词：

mitophagy;  autophagy;  MAM;  ER-mitochondrial contact site;  mitochondrial fission; 

期刊名称：

The EMBO journal.

i s s n：

0261-4189

年卷期：

2016 年 35 卷 13 期

页   码：

1368-1384

页   码：

摘   要：

In hypoxic cells, dysfunctional mitochondria are selectively removed by a specialized autophagic process called mitophagy. The ER-mitochondrial contact site (MAM) is essential for fission of mitochondria prior to engulfment, and the outer mitochondrial membrane protein FUNDC1 interacts with LC3 to recruit autophagosomes, but the mechanisms integrating these processes are poorly understood. Here, we describe a new pathway mediating mitochondrial fission and subsequent mitophagy under hypoxic conditions. FUNDC1 accumulates at the MAM by associating with the ER membrane protein calnexin. As mitophagy proceeds, FUNDC1/calnexin association attenuates and the exposed cytosolic loop of FUNDC1 interacts with DRP1 instead. DRP1 is thereby recruited to the MAM, and mitochondrial fission then occurs. Knockdown of FUNDC1, DRP1, or calnexin prevents fission and mitophagy under hypoxic conditions. Thus, FUNDC1 integrates mitochondrial fission and mitophagy at the interface of the MAM by working in concert with DRP1 and calnexin under hypoxic conditions in mammalian cells.