title: Rictor/mTORC2 deficiency enhances keratinocyte stress tolerance via mitohormesis.
abstract: 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.
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Tassone
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Saoncella
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy.|Human Genetics Foundation (HuGeF), Turin, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Neri
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy.
authors.forename: Ugo
authors.initials: U
authors.lastname: Ala
authors.affiliation: Human Genetics Foundation (HuGeF), Turin, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Brusa
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Magnuson
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy.|Center for Translational Genomics and Bioinformatics, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Paolo
authors.identifier: 0000-0001-8664-8630
authors.initials: P
authors.lastname: Provero
authors.affiliation: Human Genetics Foundation (HuGeF), Turin, Italy.|Department of Life Sciences and System Biology, University of Turin, Turin, Italy.
authors.forename: Salvatore
authors.identifier: 0000-0002-3405-765X
authors.initials: S
authors.lastname: Oliviero
authors.affiliation: Department of Oncology, University of Turin, Turin, Italy.
authors.forename: Chiara
authors.identifier: 0000-0001-9787-4836
authors.initials: C
authors.lastname: Riganti
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy.
authors.forename: Enzo
authors.initials: E
authors.lastname: Calautti
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects / Q000528:radiation effects; D015251:Epirubicin / Q000633:toxicity; D018698:Glutamic Acid / Q000378:metabolism; D006965:Hyperplasia; D053547:Keratin-14 / Q000235:genetics; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D011836:Radiation Tolerance / Q000528:radiation effects; D000076226:Rapamycin-Insensitive Companion of mTOR Protein / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives / Q000494:pharmacology; D059467:Transcriptome / Q000187:drug effects / Q000528:radiation effects; D014965:X-Rays
chemical_list: C554292:12-O-tetradecanoylphorbol-1,3-acetate; D053547:Keratin-14; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D017382:Reactive Oxygen Species; C525637:rictor protein, mouse; D018698:Glutamic Acid; D015251:Epirubicin; D013755:Tetradecanoylphorbol Acetate; D000111:Acetylcysteine