Sestrin2 Phosphorylation by ULK1 Induces Autophagic Degradation of Mitochondria Damaged by Copper-Induced Oxidative Stress

Authors

Heejeong Kim, University of Nebraska - LincolnFollow
Byeong Tak JeonFollow
Isaac M. Kim, University of Nebraska - LincolnFollow
Sydney Townsend, University of Nebraska - LincolnFollow
Carolyn M. Lorch, University of Nebraska-Lincoln & Grinnell College, Grinnell & Northwestern University, ChicagoFollow
Martonio Viana, University of Nebraska - LincolnFollow
Jacob F. Myers, University of Nebraska-Lincoln & The University of ScrantonFollow
Caroline J. Trupp, University of Nebraska-LincolnFollow
Zachary T. Whipps, University of Nebraska-LincolnFollow
Mondira Kundu, St. Jude Children’s Research Hospital, MemphisFollow
Soonkyu Chung, University of Massachusetts AmherstFollow
Xinghui Sun, University of Nebraska - LincolnFollow
Oleh Khalimonchuk, University of Nebraska-LincolnFollow
Jaekwon Lee, University of Nebraska-LincolnFollow
Seung-Hyun Ro, University of Nebraska-LincolnFollow

ORCID IDs

https://orcid.org/0000-0002-4181-8461

https://orcid.org/0000-0003-4047-3462

https://orcid.org/0000-0001-9340-6242

https://orcid.org/0000-0002-3972-8678

https://orcid.org/0000-0002-7744-7615

Date of this Version

2020

Citation

Int. J. Mol. Sci. 2020, 21, 6130; doi:10.3390/ijms21176130 www.mdpi.com/journal/ijms

Comments

2020 by the authors.

Abstract

Selective autolysosomal degradation of damaged mitochondria, also called mitophagy, is an indispensable process for maintaining integrity and homeostasis of mitochondria. One well-established mechanism mediating selective removal of mitochondria under relatively mild mitochondria-depolarizing stress is PINK1-Parkin-mediated or ubiquitin-dependent mitophagy. However, additional mechanisms such as LC3-mediated or ubiquitin-independent mitophagy induction by heavy environmental stress exist and remain poorly understood. The present study unravels a novel role of stress-inducible protein Sestrin2 in degradation of mitochondria damaged by transition metal stress. By utilizing proteomic methods and studies in cell culture and rodent models, we identify autophagy kinase ULK1-mediated phosphorylation sites of Sestrin2 and demonstrate Sestrin2 association with mitochondria adaptor proteins in HEK293 cells. We show that Ser-73 and Ser-254 residues of Sestrin2 are phosphorylated by ULK1, and a pool of Sestrin2 is strongly associated with mitochondrial ATP5A in response to Cu-induced oxidative stress. Subsequently, this interaction promotes association with LC3-coated autolysosomes to induce degradation of mitochondria damaged by Cu-induced ROS. Treatment of cells with antioxidants or a Cu chelator significantly reduces Sestrin2 association with mitochondria. These results highlight the ULK1-Sestrin2 pathway as a novel stress-sensing mechanism that can rapidly induce autophagic degradation of mitochondria under severe heavy metal stress.