Sestrin2 phosphorylation by ulk1 induces autophagic degradation of mitochondria damaged by copper-induced oxidative stress

Heejeong Kim, Byeong Tak Jeon, Isaac M. Kim, Sydney J. Bennett, Carolyn M. Lorch, Martonio Ponte Viana, Jacob F. Myers, Caroline J. Trupp, Zachary T. Whipps, Mondira Kundu, Soonkyu Chung, Xinghui Sun, Oleh Khalimonchuk, Jaekwon Lee, Seung Hyun Ro

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


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.

Original languageEnglish (US)
Article number6130
Pages (from-to)1-20
Number of pages20
JournalInternational journal of molecular sciences
Issue number17
StatePublished - Sep 1 2020


  • ATP5A
  • Autophagy
  • Mitochondria
  • Phosphorylation
  • Sestrin2
  • ULK1

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry


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