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Increased oxidative phosphorylation in response to acute and chronic DNA damage.
Brace, Lear E; Vose, Sarah C; Stanya, Kristopher; Gathungu, Rose M; Marur, Vasant R; Longchamp, Alban; Treviño-Villarreal, Humberto; Mejia, Pedro; Vargas, Dorathy; Inouye, Karen; Bronson, Roderick T; Lee, Chih-Hao; Neilan, Edward; Kristal, Bruce S; Mitchell, James R.
Afiliación
  • Brace LE; Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
  • Vose SC; Division of Environmental Health, Vermont Department of Health, Burlington, VT, USA.
  • Stanya K; Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
  • Gathungu RM; Department of Neurosurgery, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA.
  • Marur VR; Department of Neurosurgery, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA.
  • Longchamp A; Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
  • Treviño-Villarreal H; Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
  • Mejia P; Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
  • Vargas D; Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
  • Inouye K; Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
  • Bronson RT; Rodent Histopathology Core, Department of Pathology, Harvard Medical School, Boston, MA, USA.
  • Lee CH; Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
  • Neilan E; Genetics and Metabolism Division, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  • Kristal BS; Department of Neurosurgery, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA.
  • Mitchell JR; Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
NPJ Aging Mech Dis ; 2: 16022, 2016.
Article en En | MEDLINE | ID: mdl-28721274
Accumulation of DNA damage is intricately linked to aging, aging-related diseases and progeroid syndromes such as Cockayne syndrome (CS). Free radicals from endogenous oxidative energy metabolism can damage DNA, however the potential of acute or chronic DNA damage to modulate cellular and/or organismal energy metabolism remains largely unexplored. We modeled chronic endogenous genotoxic stress using a DNA repair-deficient Csa-/-|Xpa-/- mouse model of CS. Exogenous genotoxic stress was modeled in mice in vivo and primary cells in vitro treated with different genotoxins giving rise to diverse spectrums of lesions, including ultraviolet radiation, intrastrand crosslinking agents and ionizing radiation. Both chronic endogenous and acute exogenous genotoxic stress increased mitochondrial fatty acid oxidation (FAO) on the organismal level, manifested by increased oxygen consumption, reduced respiratory exchange ratio, progressive adipose loss and increased FAO in tissues ex vivo. In multiple primary cell types, the metabolic response to different genotoxins manifested as a cell-autonomous increase in oxidative phosphorylation (OXPHOS) subsequent to a transient decline in steady-state NAD+ and ATP levels, and required the DNA damage sensor PARP-1 and energy-sensing kinase AMPK. We conclude that increased FAO/OXPHOS is a general, beneficial, adaptive response to DNA damage on cellular and organismal levels, illustrating a fundamental link between genotoxic stress and energy metabolism driven by the energetic cost of DNA damage. Our study points to therapeutic opportunities to mitigate detrimental effects of DNA damage on primary cells in the context of radio/chemotherapy or progeroid syndromes.

Texto completo: 1 Banco de datos: MEDLINE Idioma: En Revista: NPJ Aging Mech Dis Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Banco de datos: MEDLINE Idioma: En Revista: NPJ Aging Mech Dis Año: 2016 Tipo del documento: Article País de afiliación: Estados Unidos