Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 21, Issue 17, Pages -Publisher
MDPI
DOI: 10.3390/ijms21176130
Keywords
autophagy; ULK1; Sestrin2; phosphorylation; mitochondria; ATP5A
Funding
- NSF-REU site [DBI-1757951]
- Undergraduate Creative Activities and Research Experience (UCARE) program-scholarship from the Pepsi Quasi Endowment and Union Bank Trust
- University of Nebraska Collaboration Initiative Grant
- University of Nebraska ARD/ORED/BIOC grants
- Layman awards
- Nebraska Tobacco Settlement Biomedical Research enhancement funds
- National Institute of General Medical Sciences of the National Institute of Health [P20GM104320]
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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.
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