title: Mitochondrial respiratory uncoupling promotes keratinocyte differentiation and blocks skin carcinogenesis.
abstract: Decreased mitochondrial oxidative metabolism is a hallmark bioenergetic characteristic of malignancy that may have an adaptive role in carcinogenesis. By stimulating proton leak, mitochondrial uncoupling proteins (UCP1-3) increase mitochondrial respiration and may thereby oppose cancer development. To test this idea, we generated a mouse model that expresses an epidermal-targeted keratin-5-UCP3 (K5-UCP3) transgene and exhibits significantly increased cutaneous mitochondrial respiration compared with wild type (FVB/N). Remarkably, we observed that mitochondrial uncoupling drove keratinocyte/epidermal differentiation both in vitro and in vivo. This increase in epidermal differentiation corresponded to the loss of markers of the quiescent bulge stem cell population, and an increase in epidermal turnover measured using a bromodeoxyuridine (BrdU)-based transit assay. Interestingly, these changes in K5-UCP3 skin were associated with a nearly complete resistance to chemically-mediated multistage skin carcinogenesis. These data suggest that targeting mitochondrial respiration is a promising novel avenue for cancer prevention and treatment.
authors.affiliation: College of Pharmacy, Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX, USA.
authors.forename: C U
authors.initials: CU
authors.lastname: Lago
authors.forename: S M
authors.initials: SM
authors.lastname: Nowinski
authors.forename: J E
authors.initials: JE
authors.lastname: Rundhaug
authors.forename: M E
authors.initials: ME
authors.lastname: Pfeiffer
authors.forename: K
authors.initials: K
authors.lastname: Kiguchi
authors.forename: K
authors.initials: K
authors.lastname: Hirasaka
authors.forename: X
authors.initials: X
authors.lastname: Yang
authors.forename: E M
authors.initials: EM
authors.lastname: Abramson
authors.forename: S B
authors.initials: SB
authors.lastname: Bratton
authors.forename: O
authors.initials: O
authors.lastname: Rho
authors.forename: R
authors.initials: R
authors.lastname: Colavitti
authors.forename: M A
authors.initials: MA
authors.lastname: Kenaston
authors.forename: T
authors.initials: T
authors.lastname: Nikawa
authors.forename: C
authors.initials: C
authors.lastname: Trempus
authors.forename: J
authors.initials: J
authors.lastname: Digiovanni
authors.forename: S M
authors.initials: SM
authors.lastname: Fischer
authors.forename: E M
authors.initials: EM
authors.lastname: Mills
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000378:metabolism*; D004817:Epidermis / Q000378:metabolism; D015870:Gene Expression; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D010101:Oxygen Consumption / Q000502:physiology; D016192:Resting Phase, Cell Cycle / Q000235:genetics; D012867:Skin / Q000378:metabolism / Q000473:pathology; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D000071247:Uncoupling Protein 3
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; C000604393:Ucp3 protein, mouse; D000071247:Uncoupling Protein 3