UVB-induced inactivation of manganese-containing superoxide dismutase promotes mitophagy via ROS-mediated mTORC2 pathway activation

Sanjit K. Dhar, Ines Batinic-Haberle, Daret K.S. Clair

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Mitochondria are major sites of energy metabolism that influence numerous cellular events, including immunity and cancer development. Previously, we reported that the mitochondrionspecific antioxidant enzyme, manganese-containing superoxide dismutase (MnSOD), has dual roles in early- and late-carcinogenesis stages. However, how defective MnSOD impacts the chain of events that lead to cell transformation in pathologically normal epidermal cells that have been exposed to carcinogens is unknown. Here, we show that UVB radiation causes nitration and inactivation ofMnSODleading to mitochondrial injury and mitophagy. In keratinocytes, exposure to UVB radiation decreased mitochondrial oxidative phosphorylation, increased glycolysis and the expression of autophagy-related genes, and enhanced AKT Ser/Thr kinase (AKT) phosphorylation and cell growth. Interestingly, UVB initiated a prosurvival mitophagy response by mitochondria-mediated reactive oxygen species (ROS) signaling via the mammalian target of the mTOR complex 2 (mTORC2) pathway. Knockdown of rictor but not raptor abrogated UVB-induced mitophagy responses. Furthermore, fractionation and proximity-ligation assays reveal that ROSmediated mTOC2 activation in mitochondria is necessary for UVB-induced mitophagy. Importantly, pretreatment with the MnSOD mimic MnTnBuOE-2-PyP5+ (MnP) attenuates mTORC2 activation and suppresses UVB-induced mitophagy. UVB radiation exposure also increased cell growth as assessed by soft-agar colony survival and cell growth assays, and pretreatment with MnP or the known autophagy inhibitor 3-methyladenine abrogated UVB-induced cell growth. These results indicate that MnSOD is a major redox regulator that maintains mitochondrial health and show that UVB-mediated MnSOD inactivation promotes mitophagy and thereby prevents accumulation of damaged mitochondria.

Original languageEnglish
Pages (from-to)6831-6842
Number of pages12
JournalJournal of Biological Chemistry
Volume294
Issue number17
DOIs
StatePublished - Apr 26 2019

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health Grant CA 214638. The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Funding Information:
Acknowledgments—We thank Dr. Mihail I. Mitov of the Redox Metabolism Shared Resource Facility (RMSRF) for outstanding technical help in acquiring data from Seahorse experiments. We acknowledge with gratitude the assistance of the RMSRF of the Markey Cancer Center, which is the recipient of National Institutes of Health Cancer Center Support Grant 2P30 CA177558 from NCI.

Publisher Copyright:
© 2019 Dhar et al.

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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