ULK1 translocates to mitochondria and phosphorylates FUNDC1 to regulate mitophagy

被引：638

作者：

Wu, Wenxian ^{[1
]}

Tian, Weili ^{[1
]}

Hu, Zhe ^{[2
]}

Chen, Guo ^{[3
]}

Huang, Lei ^{[4
]}

Li, Wen ^{[1
]}

Zhang, Xingli ^{[1
]}

Xue, Peng ^{[5
]}

Zhou, Changqian ^{[3
]}

Liu, Lei ^{[6
]}

Zhu, Yushan ^{[3
]}

Zhang, Xingliang ^{[7
]}

Li, Longxuan ^{[1
,8
]}

Zhang, Liangqing ^{[2
]}

Sui, Senfang ^{[9
]}

Zhao, Bin ^{[1
]}

Feng, Du ^{[1
]}

机构：

[1] Guangdong Med Coll, Affiliated Hosp, Inst Neurol, Guangdong Key Lab Age Related Cardiac Cerebral Va, Zhanjiang, Guangdong, Peoples R China

[2] Guangdong Med Coll, Dept Anesthesiol, Zhanjiang, Guangdong, Peoples R China

[3] Nankai Univ, Coll Life Sci, Tianjin 300071, Peoples R China

[4] Tsinghua Univ, Ctr Biomed Anal, Cell Biol Core Facil, Beijing 100084, Peoples R China

[5] Chinese Acad Sci, Inst Biophys, Beijing 100080, Peoples R China

[6] Chinese Acad Sci, Inst Zool, State Key Lab Biomembrane & Membrane Biotechnol, Beijing, Peoples R China

[7] Guangdong Med Coll, Dept Pediat, Zhanjiang, Guangdong, Peoples R China

[8] Gongli Hosp, Dept Neurol, Shanghai, Peoples R China

[9] Tsinghua Univ, Sch Life Sci, State Key Lab Biomembrane & Membrane Biotechnol, Beijing 100084, Peoples R China

来源：

EMBO REPORTS | 2014年 / 15卷 / 05期

关键词：

ULK1; mitophagy; mitochondria; mitochondrial quality control; FUNDC1; AUTOPHAGOSOME FORMATION; SELECTIVE AUTOPHAGY; MAMMALIAN-CELLS; PROTEIN; PARKIN; DEGRADATION; HYPOXIA; KINASE; ATG32; AMPK;

D O I：

10.1002/embr.201438501

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

Autophagy eliminates dysfunctional mitochondria in an intricate process known as mitophagy. ULK1 is critical for the induction of autophagy, but its substrate(s) and mechanism of action in mitophagy remain unclear. Here, we show that ULK1 is upregulated and translocates to fragmented mitochondria upon mitophagy induction by either hypoxia or mitochondrial uncouplers. At mitochondria, ULK1 interacts with FUNDC1, phosphorylating it at serine 17, which enhances FUNDC1 binding to LC3. A ULK1-binding-deficient mutant of FUNDC1 prevents ULK1 translocation to mitochondria and inhibits mitophagy. Finally, kinase-active ULK1 and a phospho-mimicking mutant of FUNDC1 rescue mitophagy in ULK1-null cells. Thus, we conclude that FUNDC1 regulates ULK1 recruitment to damaged mitochondria, where FUNDC1 phosphorylation by ULK1 is crucial for mitophagy.

引用

页码：566 / 575

页数：10

共 38 条

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The incredible ULKs [J].