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

Lookup NU author(s): Anna Smith, Dr Julia Whitehall, Carla Bradshaw, Dr Fiona Robertson, Dr Alasdair Blain, Dr Gavin Hudson, Dr Angela Pyle, Dr Dave Houghton, Matthew Hunt, Dr James Sampson, Dr Craig Stamp, Grace Mallett, Dr Shoba Amarnath, Dr Jack Leslie, Professor Fiona Oakley, Laura Wilson, Angela Baker, Dr Oliver Russell, Riem Johnson, Dr Claire Richardson, Dr Iain McCallum, Seamus Kelly, Professor John Mathers, Professor Rakesh Heer, Professor Robert Taylor, Professor Neil Perkins, Emeritus Professor Doug Turnbull, Dr Laura Greaves

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This is the authors' accepted manuscript of an article that has been published in its final definitive form by Nature, 2020.

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Abstract

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.


Publication metadata

Author(s): 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

Publication type: Article

Publication status: Published

Journal: Nature Cancer

Year: 2020

Volume: 1

Pages: 976-989

Print publication date: 01/10/2020

Online publication date: 21/09/2020

Acceptance date: 05/08/2020

Date deposited: 13/11/2020

ISSN (electronic): 2662-1347

Publisher: Nature

URL: https://doi.org/10.1038/s43018-020-00112-5

DOI: 10.1038/s43018-020-00112-5


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