期刊
NATURE CANCER
卷 1, 期 10, 页码 976-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s43018-020-00112-5
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- Newcastle University Bioimaging Unit
- Wellcome Centre for Mitochondrial Research [203105/Z/16/Z]
- Newcastle University Centre for Ageing and Vitality - Biotechnology and Biological Sciences Research Council
- Engineering and Physical Sciences Research Council
- Economic and Social Research Council
- Medical Research Council [MR/L016354/1, MR/R023026/1]
- UK NIHR Biomedical Research Centre Age and Age Related Diseases award
- NC3Rs [NC/K500513/1]
- Cancer Research UK [A25045, A17196, A12481, A21139, C18342, A23390]
- ERC [311301]
- MRC [MR/T015586/1, MR/K001949/1, MR/R023026/1] Funding Source: UKRI
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.
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