Aging-Related Defects in Oxidative Phosphorylation May Be Tumorigenic

Defects in mitochondrial oxidative phosphorylation (OXPHOS) commonly occur with age due to accumulation of mutations in mitochondrial DNA, which encodes 13 essential components of the OXPHOS system. OXPHOS is also often defective in cancer; however, whether aging-related OXPHOS dysfunction is linked to cancer is unknown. Smith, Whitehall, and colleagues investigated this, focusing on colorectal cancer due to the especially high prevalence of OXPHOS defects in aging colorectal epithelium and the fact that the most impactful risk factor for colorectal cancer is advanced age. In human colorectal adenomas, adenocarcinomas, and patient-matched normal crypts, immunohistochemical analyses of a subunit of each of the four mitochondrial complexes and histochemical analyses of cytochrome c oxidase (COX) reactivity revealed loss or decreased levels of one or more mitochondrial subunits and/or loss of COX reactivity in 44% of adenomas and 69% of adenocarcinomas but only 10% of healthy crypts. Mitochondrial-DNA analysis demonstrated that 82% of OXPHOS-deficient tumors harbored mitochondrial-DNA mutations at high levels of heteroplasmy that explained the OXPHOS deficiency. The mutational spectrum was similar between normal aged colonic crypts and tumors. To determine whether the observed OXPHOS defects conferred a metabolic advantage to tumor cells, an Apc-mutant inducible intestinal tumor mouse model with a mutation in the catalytic subunit of mitochondrial polymerase γ (encoded by PolgA) that causes rapid mitochondrial mutagenesis and resulting OXPHOS dysfunction was employed. Compared with Apc-mutant PolgA–wild-type mice, Apc-mutant PolgA-mutant mice had increased tumor growth due to enhanced tumor-cell proliferation and reduced apoptosis, leading to shorter life span in the double-mutant mice. Further, small-intestinal adenomas from double-mutant mice were deficient in mitochondrial Complex I, but not Complex II, III, or IV. In both normal crypts and adenomas, OXPHOS defects caused upregulation of de novo serine biosynthesis, an observation replicated in normal aging human colonic crypts. In summary, this work shows that aging-related OXPHOS dysfunction may contribute to the development of intestinal cancer.

Smith ALM, Whitehall JC, Bradshaw C, Gay D, Robertson F, Blain AP, et al. Age-associated mitochondrial DNA mutations cause metabolic remodeling that contributes to accelerated intestinal tumorigenesis. Nat Cancer 2020 Sep 21 [Epub ahead of print].

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