Publication

Pleiotropic age-dependent effects of mitochondrial dysfunction on epidermal stem cells

Velarde, M. C., Demaria, M., Melov, S. & Campisi, J., 18-Aug-2015, In : Proceedings of the National Academy of Sciences of the United States of America. 112, 33, p. 10407-12 6 p.

Research output: Contribution to journalArticleAcademicpeer-review

Tissue homeostasis declines with age partly because stem/progenitor cells fail to self-renew or differentiate. Because mitochondrial damage can accelerate aging, we tested the hypothesis that mitochondrial dysfunction impairs stem cell renewal or function. We developed a mouse model, Tg(KRT14-cre/Esr1) (20Efu/J) × Sod2 (tm1Smel) , that generates mitochondrial oxidative stress in keratin 14-expressing epidermal stem/progenitor cells in a temporally controlled manner owing to deletion of Sod2, a nuclear gene that encodes the mitochondrial antioxidant enzyme superoxide dismutase 2 (Sod2). Epidermal Sod2 loss induced cellular senescence, which irreversibly arrested proliferation in a fraction of keratinocytes. Surprisingly, in young mice, Sod2 deficiency accelerated wound closure, increasing epidermal differentiation and reepithelialization, despite the reduced proliferation. In contrast, at older ages, Sod2 deficiency delayed wound closure and reduced epidermal thickness, accompanied by epidermal stem cell exhaustion. In young mice, Sod2 deficiency accelerated epidermal thinning in response to the tumor promoter 12-O-tetradecanoylphorbol-13-acetate, phenocopying the reduced regeneration of older Sod2-deficient skin. Our results show a surprising beneficial effect of mitochondrial dysfunction at young ages, provide a potential mechanism for the decline in epidermal regeneration at older ages, and identify a previously unidentified age-dependent role for mitochondria in skin quality and wound closure.

Original languageEnglish
Pages (from-to)10407-12
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number33
Publication statusPublished - 18-Aug-2015
Externally publishedYes

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