CDK4-mediated MnSOD activation and mitochondrial homeostasis in radioadaptive protection

Cuihong Jin, Lili Qin, Yan Shi, Demet Candas, Ming Fan, Chung Ling Lu, Andrew T M Vaughan, Rulong Shen, Larry S. Wu, Rui Liu, Robert F. Li, Jeffrey S. Murley, Gayle Woloschak, David J. Grdina, Jian-Jian Li

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

Mammalian cells are able to sense environmental oxidative and genotoxic conditions such as the environmental low-dose ionizing radiation (LDIR) present naturally on the earth's surface. The stressed cells then can induce a so-called radioadaptive response with an enhanced cellular homeostasis and repair capacity against subsequent similar genotoxic conditions such as a high dose radiation. Manganese superoxide dismutase (MnSOD), a primary mitochondrial antioxidant in mammals, has long been known to play a crucial role in radioadaptive protection by detoxifying O2 •- generated by mitochondrial oxidative phosphorylation. In contrast to the well-studied mechanisms of SOD2 gene regulation, the mechanisms underlying posttranslational regulation of MnSOD for radioprotection remain to be defined. Herein, we demonstrate that cyclin D1/cyclin-dependent kinase 4 (CDK4) serves as the messenger to deliver the stress signal to mitochondria to boost mitochondrial homeostasis in human skin keratinocytes under LDIR-adaptive radioprotection. Cyclin D1/CDK4 relocates to mitochondria at the same time as MnSOD enzymatic activation peaks without significant changes in total MnSOD protein level. The mitochondrial-localized CDK4 directly phosphorylates MnSOD at serine-106 (S106), causing enhanced MnSOD enzymatic activity and mitochondrial respiration. Expression of mitochondria-targeted dominant negative CDK4 or the MnSOD-S106 mutant reverses LDIR-induced mitochondrial enhancement and adaptive protection. The CDK4-mediated MnSOD activation and mitochondrial metabolism boost are also detected in skin tissues of mice receiving in vivo whole-body LDIR. These results demonstrate a unique CDK4-mediated mitochondrial communication that allows cells to sense environmental genotoxic stress and boost mitochondrial homeostasis by enhancing phosphorylation and activation of MnSOD.

Original languageEnglish (US)
Pages (from-to)77-87
Number of pages11
JournalFree Radical Biology and Medicine
Volume81
DOIs
StatePublished - 2015

Keywords

  • Cyclin D1/CDK4
  • Free radicals
  • Mitochondrial homeostasis
  • MnSOD
  • Phosphorylation
  • Radioadaptive response

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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    Jin, C., Qin, L., Shi, Y., Candas, D., Fan, M., Lu, C. L., Vaughan, A. T. M., Shen, R., Wu, L. S., Liu, R., Li, R. F., Murley, J. S., Woloschak, G., Grdina, D. J., & Li, J-J. (2015). CDK4-mediated MnSOD activation and mitochondrial homeostasis in radioadaptive protection. Free Radical Biology and Medicine, 81, 77-87. https://doi.org/10.1016/j.freeradbiomed.2014.12.026