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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

34 Scopus citations


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
StatePublished - Apr 2015


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

ASJC Scopus subject areas

  • Physiology (medical)
  • Biochemistry


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