Sestrin2 Phosphorylation by ULK1 Induces Autophagic Degradation of Mitochondria Damaged by Copper-Induced Oxidative Stress
| العنوان: | Sestrin2 Phosphorylation by ULK1 Induces Autophagic Degradation of Mitochondria Damaged by Copper-Induced Oxidative Stress |
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| المؤلفون: | Heejeong Kim, Mondira Kundu, Isaac M. Kim, Byeong Tak Jeon, Martonio Ponte Viana, Jaekwon Lee, Soonkyu Chung, Jacob F. Myers, Oleh Khalimonchuk, Xinghui Sun, Caroline J. Trupp, Zachary T. Whipps, Carolyn M. Lorch, Sydney J. Bennett, Seung Hyun Ro |
| المصدر: | International Journal of Molecular Sciences, Vol 21, Iss 6130, p 6130 (2020) International Journal of Molecular Sciences Volume 21 Issue 17 |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Proteomics, Sestrin2, Mitochondrion, medicine.disease_cause, Article, Catalysis, Inorganic Chemistry, lcsh:Chemistry, Mitophagy, medicine, Autophagy, Autophagy-Related Protein-1 Homolog, Humans, Physical and Theoretical Chemistry, Phosphorylation, Molecular Biology, lcsh:QH301-705.5, Spectroscopy, ULK1, Binding Sites, Chemistry, Kinase, Organic Chemistry, Intracellular Signaling Peptides and Proteins, Signal transducing adaptor protein, Nuclear Proteins, ATP5A, General Medicine, Mitochondrial Proton-Translocating ATPases, Computer Science Applications, Cell biology, Mitochondria, Oxidative Stress, HEK293 Cells, lcsh:Biology (General), lcsh:QD1-999, Microtubule-Associated Proteins, Oxidative stress, Copper, Signal Transduction |
| الوصف: | 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. |
| وصف الملف: | application/pdf |
| تدمد: | 1422-0067 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::174c48baeb812dc7c3cd2cf2bfb54a3dTest https://pubmed.ncbi.nlm.nih.gov/32854424Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....174c48baeb812dc7c3cd2cf2bfb54a3d |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14220067 |
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