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

Authors

Heejeong Kim, University of Nebraska - LincolnFollow
Byeong Tak Jeon, University of Nebraska - LincolnFollow
Isaac M. Kim, University of Nebraska - LincolnFollow
Sydney J. Bennett, University of Nebraska - LincolnFollow
Carolyn M. Lorch, University of Nebraska - LincolnFollow
Martonio Ponte Viana, University of Nebraska - LincolnFollow
Jacob F. Myers, University of ScrantonFollow
Caroline J. Trupp, University of Nebraska - LincolnFollow
Zachary T. Whipps, University of Nebraska - LincolnFollow
Mondira Kundu, St. Jude Children's Research HospitalFollow
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

Publication Date

2020

Journal or Book Title

International Journal of Molecular Sciences

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.

DOI

https://doi.org/10.3390/ijms21176130

Volume

21

Special Issue

Autophagy in Health, Ageing and Disease 2.0

Issue

17

License

UMass Amherst Open Access Policy

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

Recommended Citation

Kim, Heejeong; Jeon, Byeong Tak; Kim, Isaac M.; Bennett, Sydney J.; Lorch, Carolyn M.; Viana, Martonio Ponte; Myers, Jacob F.; Trupp, Caroline J.; Whipps, Zachary T.; Kundu, Mondira; Chung, Soonkyu; Sun, Xinghui; Khalimonchuk, Oleh; Lee, Jaekwon; and Ro, Seung-Hyun, "Sestrin2 Phosphorylation by ULK1 Induces Autophagic Degradation of Mitochondria Damaged by Copper-Induced Oxidative Stress" (2020). International Journal of Molecular Sciences. 231.
https://doi.org/10.3390/ijms21176130