Rictor/mTORC2 deficiency enhances keratinocyte stress tolerance via mitohormesis.

Tassone B, Saoncella S, Neri F, Ala U, Brusa D, Magnuson MA, Provero P, Oliviero S, Riganti C, Calautti E
Cell Death Differ. 2017 24 (4): 731-746

PMID: 28211872 · PMCID: PMC5384034 · DOI:10.1038/cdd.2017.8

How metabolic pathways required for epidermal tissue growth and remodeling influence the ability of keratinocytes to survive stressful conditions is still largely unknown. The mechanistic target of rapamycin complex 2 (mTORC2) regulates growth and metabolism of several tissues, but its functions in epidermal cells are poorly defined. Rictor is an adaptor protein essential for mTORC2 activity. To explore the roles of mTORC2 in the epidermis, we have conditionally deleted rictor in mice via K14-Cre-mediated homologous recombination and found that its deficiency causes moderate tissue hypoplasia, reduced keratinocyte proliferation and attenuated hyperplastic response to TPA. Noteworthy, rictor-deficient keratinocytes displayed increased lifespan, protection from senescence, and enhanced tolerance to cellular stressors such as growth factors deprivation, epirubicin and X-ray in vitro and radioresistance in vivo. Rictor-deficient keratinocytes exhibited changes in global gene expression profiles consistent with metabolic alterations and enhanced stress tolerance, a shift in cell catabolic processes from glycids and lipids to glutamine consumption and increased production of mitochondrial reactive oxygen species (ROS). Mechanistically, the resiliency of rictor-deficient epidermal cells relies on these ROS increases, indicating stress resistance via mitohormesis. Thus, our findings reveal a new link between metabolic changes and stress adaptation of keratinocytes centered on mTORC2 activity, with potential implications in skin aging and therapeutic resistance of epithelial tumors.

MeSH Terms (22)

Acetylcysteine Animals Apoptosis Cell Proliferation Cells, Cultured Cellular Senescence Epirubicin Glutamic Acid Hyperplasia Keratin-14 Keratinocytes Mice Mice, Inbred C57BL Mice, Knockout Mitochondria Radiation Tolerance Rapamycin-Insensitive Companion of mTOR Protein Reactive Oxygen Species Skin Tetradecanoylphorbol Acetate Transcriptome X-Rays

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