Open AccessAge-associated mitochondrial DNA mutations cause metabolic remodeling that contributes to accelerated intestinal tumorigenesis
Author(s) -
Anna Smith,
Julia C Whitehall,
Carla Bradshaw,
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,
S. B. Kelly,
J Mathers,
Rakesh Heer,
Robert W. Taylor,
Neil D. Perkins,
D.M. Turnbull,
Owen J. Sansom,
Laura C. Greaves
Publication year - 2020
Publication title -
nature cancer
Language(s) - English
Resource type - Journals
ISSN - 2662-1347
DOI - 10.1038/s43018-020-00112-5
Subject(s) - carcinogenesis , biology , mitochondrial dna , oxidative phosphorylation , cancer research , mutation , mitochondrion , colorectal cancer , dna damage , somatic cell , cancer , genetics , gene , dna , biochemistry
Oxidative phosphorylation (OXPHOS) defects caused by somatic mitochondrial DNA (mtDNA) mutations increase with age in human colorectal epithelium and are prevalent in colorectal tumours, but whether they actively contribute to tumorigenesis remains unknown. Here we demonstrate that mtDNA mutations causing OXPHOS defects are enriched during the human adenoma/carcinoma sequence, suggesting they may confer a metabolic advantage. To test this we deleted the tumour suppressor Apc in OXPHOS deficient intestinal stem cells in mice. The resulting tumours were larger than in control mice due to accelerated cell proliferation and reduced apoptosis. We show that both normal crypts and tumours undergo metabolic remodelling in response to OXPHOS deficiency by upregulating the de novo serine synthesis pathway (SSP). Moreover, normal human colonic crypts upregulate the SSP in response to OXPHOS deficiency prior to tumorigenesis. Our data show that age-associated OXPHOS deficiency causes metabolic remodelling that can functionally contribute to accelerated intestinal cancer development.