A regulatory signaling loop comprising the PGAM5 phosphatase and CK2 controls receptor-mediated mitophagy.

Abstract

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.

• Authors: Guo Chen, Zhe Han, Du Feng, Yanfang Chen, Linbo Chen, Hao Wu, Li Huang, Changqian Zhou, Xiangyu Cai, Changying Fu, Liangwei Duan, Xiaohui Wang, Lei Liu, Xinqi Liu, Yuequan Shen, Yushan Zhu, Quan Chen
• Journal: Molecular cell (Mol Cell) Vol. 54 Issue 3 Pg. 362-77 (May 08 2014) ISSN: 1097-4164 [Electronic] United States
• PMID: 24746696 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Carrier Proteins
• FUNDC1 protein, human
• MAP1LC3A protein, human
• Membrane Proteins
• Microtubule-Associated Proteins
• Mitochondrial Proteins
• Casein Kinase II
• PGAM5 protein, human
• Phosphoprotein Phosphatases

Topics

• Amino Acid Sequence
• Carrier Proteins (metabolism)
• Casein Kinase II (metabolism)
• Consensus Sequence
• Feedback, Physiological
• HeLa Cells
• Humans
• Membrane Proteins (chemistry, metabolism)
• Microtubule-Associated Proteins (metabolism)
• Mitochondrial Proteins (chemistry, metabolism)
• Mitophagy
• Molecular Sequence Data
• Phosphoprotein Phosphatases
• Phosphorylation
• Protein Processing, Post-Translational