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

ageing cancer cancer genomics cancer metabolism energy metabolism

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#1 Engadin

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Posted 22 September 2020 - 02:21 PM


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F U L L   T I T L E :   Age-associated mitochondrial DNA mutations cause metabolic remodeling that contributes to accelerated intestinal tumorigenesis

 

 

 

P A Y W A L L E D   S O U R C E :   nature

 

 

 

 

 

 

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.
 
 
 
 
 
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Edited by Engadin, 22 September 2020 - 02:22 PM.






Also tagged with one or more of these keywords: ageing, cancer, cancer genomics, cancer metabolism, energy metabolism

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