Age-associated mitochondrial DNA mutations cause metabolic remodeling that contributes to accelerated intestinal tumorigenesis
| Title: | Age-associated mitochondrial DNA mutations cause metabolic remodeling that contributes to accelerated intestinal tumorigenesis |
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| Authors: | Smith ALM; Whitehall JC; Bradshaw C; Gay D; Robertson F; Blain AP; Hudson G; Pyle A; Houghton D; Hunt M; Sampson JN; Stamp C; Mallett G; Amarnath S; Leslie J; Oakley F; Wilson L; Baker A; Russell OM; Johnson R; Richardson CA; Gupta B; McCallum I; McDonald SAC; Kelly S; Mathers JC; Heer R; Taylor RW; Perkins ND; Turnbull DM; Sansom OJ; Greaves LC |
| Source: | Nature Cancer |
| Publisher Information: | Nature |
| Collection: | Newcastle University Library ePrints Service |
| Description: | 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. |
| Document Type: | article in journal/newspaper |
| File Description: | application/pdf |
| Language: | unknown |
| Relation: | https://eprints.ncl.ac.uk/270938; https://eprints.ncl.ac.uk/fulltext.aspx?url=270938/3FF2DE4B-8557-49CA-8F34-6BDBB633EB05.pdf&pub_id=270938 |
| Availability: | https://eprints.ncl.ac.uk/270938 |
| Accession Number: | edsbas.C17DD20B |
| Database: | BASE |