@article{cdb477ab75be4c2da0b8ca1368b4e016,
title = "Sestrin2 phosphorylation by ulk1 induces autophagic degradation of mitochondria damaged by copper-induced oxidative stress",
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.",
keywords = "ATP5A, Autophagy, Mitochondria, Phosphorylation, Sestrin2, ULK1",
author = "Heejeong Kim and Jeon, {Byeong Tak} and Kim, {Isaac M.} and Bennett, {Sydney J.} and Lorch, {Carolyn M.} and Viana, {Martonio Ponte} and Myers, {Jacob F.} and Trupp, {Caroline J.} and Whipps, {Zachary T.} and Mondira Kundu and Soonkyu Chung and Xinghui Sun and Oleh Khalimonchuk and Jaekwon Lee and Ro, {Seung Hyun}",
note = "Funding Information: Funding: This work was supported by NSF-REU site (DBI-1757951) to C.M.L. and J.F.M.; Undergraduate Creative Activities and Research Experience (UCARE) program-scholarship from the Pepsi Quasi Endowment and Union Bank & Trust to S.J.B., C.J.T., and Z.T.W.; University of Nebraska Collaboration Initiative Grant to J.L. and S-H.R.; University of Nebraska ARD/ORED/BIOC grants, Layman awards, Nebraska Tobacco Settlement Biomedical Research enhancement funds to S-H. R. This research was supported in part by funding from the National Institute of General Medical Sciences of the National Institute of Health under Award Number (P20GM104320). Funding Information: This work was supported by NSF-REU site (DBI-1757951) to C.M.L. and J.F.M.; Undergraduate Creative Activities and Research Experience (UCARE) program-scholarship from the Pepsi Quasi Endowment and Union Bank & Trust to S.J.B., C.J.T., and Z.T.W.; University of Nebraska Collaboration Initiative Grant to J.L. and S-H.R.; University of Nebraska ARD/ORED/BIOC grants, Layman awards, Nebraska Tobacco Settlement Biomedical Research enhancement funds to S-H. R. This research was supported in part by funding from the National Institute of General Medical Sciences of the National Institute of Health under Award Number (P20GM104320). We thank D. H. Kim (University of Minnesota-Twin Cities, USA), J. H. Lee (University of Michigan at Ann Arbor, USA), and P. N. Black, D. F. Becker, J. Zempleni, R. Franco-Cruz, and E. Harris [University of Nebraska-Lincoln (UNL), USA] for sharing DNA constructs, cell lines, mouse protocol, reagents, and access to lab equipment. We thank former and current Ro lab members for technical assistance and helpful discussion. We thank S. Alvarez and M. Naldrett at the Proteomics and Metabolomics Facility, Center for Biotechnology at UNL for the proteomics analysis. The facility and instrumentation were supported by the Nebraska Research Initiative. We are thankful to Y. Zhou and staff from Microscopy core at UNL. Publisher Copyright: {\textcopyright} 2020 by the authors. Licensee MDPI, Basel, Switzerland.",
year = "2020",
month = sep,
day = "1",
doi = "10.3390/ijms21176130",
language = "English (US)",
volume = "21",
pages = "1--20",
journal = "International Journal of Molecular Sciences",
issn = "1661-6596",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "17",
}