TY - JOUR TI - Age-associated mitochondrial DNA mutations cause metabolic remodeling that contributes to accelerated intestinal tumorigenesis AU - Smith, Anna L. M. AU - Whitehall, Julia C. AU - Bradshaw, Carla AU - Gay, David AU - Robertson, Fiona AU - Blain, Alasdair P. AU - Hudson, Gavin AU - Pyle, Angela AU - Houghton, David AU - Hunt, Matthew AU - Sampson, James N. AU - Stamp, Craig AU - Mallett, Grace AU - Amarnath, Shoba AU - Leslie, Jack AU - Oakley, Fiona AU - Wilson, Laura AU - Baker, Angela AU - Russell, Oliver M. AU - Johnson, Riem AU - Richardson, Claire A. AU - Gupta, Bhavana AU - McCallum, Iain AU - McDonald, Stuart A. C. AU - Kelly, Seamus AU - Mathers, John C. AU - Heer, Rakesh AU - Taylor, Robert W. AU - Perkins, Neil D. AU - Turnbull, Doug M. AU - Sansom, Owen J. AU - Greaves, Laura C. T2 - Nature Cancer AB - Oxidative phosphorylation (OXPHOS) defects caused by somatic mitochondrial DNA mutations increase with age in human colorectal epithelium and are prevalent in colorectal tumors, but whether they actively contribute to tumorigenesis remains unknown. Here we demonstrate that mitochondrial DNA mutations causing OXPHOS defects are enriched during the human adenoma/carcinoma sequence, suggesting that they may confer a metabolic advantage. To test this, we deleted the tumor suppressor Apc in OXPHOS-deficient intestinal stem cells in mice. The resulting tumors were larger than in control mice due to accelerated cell proliferation and reduced apoptosis. We show that both normal crypts and tumors undergo metabolic remodeling in response to OXPHOS deficiency by upregulating the de novo serine synthesis pathway. Moreover, normal human colonic crypts upregulate the serine synthesis pathway in response to OXPHOS deficiency before tumorigenesis. Our data show that age-associated OXPHOS deficiency causes metabolic remodeling that can functionally contribute to accelerated intestinal cancer development. DA - 2020/09/21/ PY - 2020 DO - 10.1038/s43018-020-00112-5 DP - www.nature.com SP - 1 EP - 14 LA - en SN - 2662-1347 UR - https://www.nature.com/articles/s43018-020-00112-5 Y2 - 2020/09/22/16:44:27 ER -