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

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作者
Anna L. M. Smith
Julia C. Whitehall
Carla Bradshaw
David Gay
Fiona Robertson
Alasdair P. 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 A. Richardson
Bhavana Gupta
Iain McCallum
Stuart A. C. McDonald
Seamus Kelly
John C. Mathers
Rakesh Heer
Robert W. Taylor
Neil D. Perkins
Doug M. Turnbull
Owen J. Sansom
Laura C. Greaves
机构
[1] Newcastle University,Wellcome Centre for Mitochondrial Research
[2] Newcastle University,Biosciences Institute
[3] Cancer Research UK Beatson Institute,Institute of Cancer Sciences
[4] University of Glasgow,Translational and Clinical Research Institute
[5] Newcastle University,Newcastle Fibrosis Research Group
[6] Biosciences Institute,Newcastle Cancer Centre, Translational and Clinical Research Institute
[7] Newcastle University,Centre for Tumour Biology, Barts Cancer Institute
[8] Queen Mary University of London,Human Nutrition Research Centre, Population Health Sciences Institute
[9] Newcastle University,undefined
来源
Nature Cancer | 2020年 / 1卷
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摘要
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.
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页码:976 / 989
页数:13
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