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Age-associated mitochondrial DNA mutations cause metabolic remodeling that contributes to accelerated intestinal tumorigenesis

2020; Nature Portfolio; Volume: 1; Issue: 10 Linguagem: Inglês

10.1038/s43018-020-00112-5

2662-1347

Anna L. Smith, Julia C. Whitehall, Carla Bradshaw, David M. Gay, Fiona Robertson, Alasdair Blain, Gavin Hudson, Angela Pyle, David Houghton, Matthew Hunt, James N. Sampson, Craig Stamp, Grace Mallett, Shoba Amarnath, Jack Leslie, Fiona Oakley, Laura Wilson, Angela Baker, Oliver M. Russell, Riem Johnson, Claire Richardson, Bhavana Gupta, Iain McCallum, Stuart McDonald, Seamus B. Kelly, John C. Mathers, Rakesh Heer, Robert W. Taylor, Neil D. Perkins, Douglass M. Turnbull, Owen J. Sansom, Laura C. Greaves,

RNA modifications and cancer

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. Smith et al. report that age-associated mutations in mitochondrial DNA cause defects in oxidative phosphorylation. This results in metabolic rewiring, which subsequently contributes to accelerated development of colorectal cancer.