A Regulatory Signaling Loop Comprising the PGAM5 Phosphatase and CK2 Controls Receptor-Mediated Mitophagy

• Published in: Molecular cell Vol. 54; no. 3; pp. 362 - 377
• Main Authors: Chen, Guo, Han, Zhe, Feng, Du, Chen, Yanfang, Chen, Linbo, Wu, Hao, Huang, Li, Zhou, Changqian, Cai, Xiangyu, Fu, Changying, Duan, Liangwei, Wang, Xiaohui, Liu, Lei, Liu, Xinqi, Shen, Yuequan, Zhu, Yushan, Chen, Quan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.05.2014
• Subjects: Amino Acid Sequence; autophagy; Carrier Proteins - metabolism; Casein Kinase II - metabolism; Consensus Sequence; dephosphorylation; Feedback, Physiological; HeLa Cells; Humans; hypoxia; Membrane Proteins - chemistry; Membrane Proteins - metabolism; Microtubule-Associated Proteins - metabolism; mitochondria; Mitochondrial Degradation; Mitochondrial Proteins - chemistry; Mitochondrial Proteins - metabolism; Molecular Sequence Data; Phosphoprotein Phosphatases; Phosphorylation; Protein Processing, Post-Translational; quality control; receptors; serine; signal transduction
• ISSN: 1097-2765; 1097-4164; 1097-4164
• DOI: 10.1016/j.molcel.2014.02.034

Mitochondrial autophagy, or mitophagy, is a major mechanism involved in mitochondrial quality control via selectively removing damaged or unwanted mitochondria. Interactions between LC3 and mitophagy receptors such as FUNDC1, which harbors an LC3-interacting region (LIR), are essential for this selective process. However, how mitochondrial stresses are sensed to activate receptor-mediated mitophagy remains poorly defined. Here, we identify that the mitochondrially localized PGAM5 phosphatase interacts with and dephosphorylates FUNDC1 at serine 13 (Ser-13) upon hypoxia or carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP) treatment. Dephosphorylation of FUNDC1 catalyzed by PGAM5 enhances its interaction with LC3, which is abrogated following knockdown of PGAM5 or the introduction of a cell-permeable unphosphorylated peptide encompassing the Ser-13 and LIR of FUNDC1. We further observed that CK2 phosphorylates FUNDC1 to reverse the effect of PGAM5 in mitophagy activation. Our results reveal a mechanistic signaling pathway linking mitochondria-damaging signals to the dephosphorylation of FUNDC1 by PGAM5, which ultimately induces mitophagy. [Display omitted] •FUNDC1 dephosphorylation at Ser-13 activates mitophagy•PGAM5 and CK2 regulate the reversible phosphorylation of FUNDC1•Knockdown of PGAM5 abrogates receptor-mediated mitophagy•CK2 and Src kinase functionally cooperate to regulate FUNDC1-mediated mitophagy Mitochondrial autophagy, or mitophagy, is a major mechanism involved in mitochondrial quality control. Chen et al. describe a regulatory signaling loop comprising the PGAM5 phosphatase and CK2 that controls receptor-mediated mitophagy.