Mitochondrial DNA damage, metabolic disruption and aging have all been associated with cancer. These three threads are now woven together to show that aging-associated somatic mutations to mitochondrial DNA alter mitochondrial serine metabolism to support cell transformation and colon-cancer development.
Mitochondrial defects are known to contribute to diverse chronic pathologies, including some that are not caused exclusively by dysregulated energy metabolism1, such as cancer. A large body of literature links mitochondrial DNA (mtDNA) damage to the cumulative decline in cell and tissue function that comes with time2. mtDNA encodes essential components of the mitochondrial oxidative-phosphorylation machinery and is particularly susceptible to damage, such as oxidative damage due to exposure to reactive oxygen species. The fact that mtDNA mutations accumulate with age2,3 and can be caused by reactive oxygen species gave rise to an extension to the free-radical theory of aging, in which mtDNA mutations disrupt the respiratory chain and thus elevate the production of reactive oxygen species, which subsequently leads to further mtDNA damage and ultimately underpins the aging process2. This simple explanation of aging is not viable, given that the amount of mtDNA mutations that accumulate with age is on average not sufficient to disrupt mitochondrial function in a tissue4. Thus, whether mtDNA damage is simply a consequence of aging or mtDNA mutations functionally contribute to this process is not fully resolved.
As age is the biggest risk factor for the development of cancer5, the role of mtDNA mutations in tumorigenesis is of considerable interest. High levels of mtDNA mutations have been reported for a number of tumor types6,7, and potentially arise from the clonal expansion of cells containing mtDNA mutations. Whether the accumulation of mutated mtDNA in these tumors is a consequence of their rapid cell division, or whether mtDNA mutations gave a selective advantage to transformed cells that contributes to cancer development and progression, such as by affecting mitochondrial metabolism in that cell lineage6,7, remains an important open question. In this issue of Nature Cancer, Smith et al. explore the ways mitochondria can affect cancer by showing that aging-associated mtDNA mutations lead to upregulated serine metabolism and thereby sustain colonic crypt cells on their path to becoming tumors8 (Fig. 1).
The authors followed up on previous work that explored changes in colon crypts where cells divide rapidly and accumulate mtDNA mutations with age, which results in impaired respiratory-chain activity and deficiency in oxidative phosphorylation9. In the present study, they sought to determine whether the accumulation of mtDNA mutations in these rapidly dividing cells drove the subsequent formation of cancer or whether these mutations were secondary to segregation of mtDNA between rapidly divided cells. To that end, they first showed that in many adenocarcinomas from patients, there was an accumulation of mtDNA mutations relative to their abundance in the surrounding tissue. To test whether these mtDNA mutations helped sustain the cancer cells, they employed an inducible intestinal tumorigenesis mouse model in which the tumor suppressor–encoding gene Apc (adenomatous polyposis coli) is knocked out in intestinal stem cells, which makes these mice more susceptible to colon cancer due to defective apoptosis. They crossed this mouse with the PolgAmut/mut ‘mutator’ mouse model10; this model has an mtDNA polymerase that lacks its proofreading ability, which leads to accelerated mtDNA mutagenesis. Thus, this model enabled Smith et al. to test how the accumulation of mtDNA mutations with age contributed to tumor formation8. They found that selectively knocking down Apc in intestinal stem cells drove intestinal tumor formation and that this was further accelerated by the PolgAmut/mut mutation. This enhancement in tumorigenesis was associated with a large proportion of mtDNA mutations in the tumors. Furthermore, the increased load of defective mtDNA decreased the oxidative-phosphorylation capacity of the cells and led to an upregulation of the serine-synthesis pathway. The increased metabolic flux through this pathway was probably a stress response to the defect in oxidative phosphorylation, as serine metabolism helps to sustain the antioxidant defenses within the cell11. Increased serine biogenesis in Apc-driven intestinal tumors has been shown previously12, and here, Smith et al. found that serine synthesis was elevated in mtDNA mutants before tumorigenesis8. Thus, they concluded that intestinal stem cells with mtDNA mutations that lead to deficiencies in oxidative phosphorylation rewire their metabolism to increase de novo serine synthesis, which confers a metabolic advantage in tumorigenesis that increases cell proliferation and reduces apoptosis and thereby favors cancer development.
Although this study is important in helping to delineate the role of mtDNA mutations in cancer development, much remains to be discovered. A caveat of the present work is that the PolgAmut/mut mutator mouse used is a global knock-in model, so mtDNA mutations are induced throughout the mouse and not selectively in the colonic epithelium. Thus, the possibility has not been excluded that rather than being intrinsic to the colon cells that ultimately develop into tumors, the observed effects may be influenced by interactions and signals from sources other than the gut, such as the immune system or metabolites from other tissues. A more selective approach to the introduction of mtDNA mutations, such as the use of emerging genetic approaches to specifically manipulate mtDNA13, may help to further define the role of mtDNA mutations in tumorigenesis. As the effects of Apc tumor-suppressor mutations manifest predominantly in the colon, this also raises the question of whether mtDNA is a driver of tumor initiation in other cancer types. Colonic crypts, with their rapidly dividing cells and the accumulation of somatic mtDNA mutations9, provide an environment well suited for such mtDNA-dependent tumor-promoting mechanisms to arise. Whether other cell types, which are likely to develop mtDNA mutations at a much slower rate, are similarly conducive, and thus whether this represents a conserved mechanism in the development of cancer, remains unknown for now. Also, whether mtDNA mutations in other tissue types may foster tumorigenesis through upregulation of the serine-synthesis pathway as they do in colon tumors or by alternative mechanisms requires exploration.
The present findings also highlight the fact that the interplay between somatic mtDNA mutations and cancer is far from simple. For instance, no increase in tumor incidence was seen in the PolgAmut/mut mice in the absence of Apc mutation. In addition, no clear link has been observed between patients with a primary mitochondrial disease and cancer14. Thus, mtDNA mutations appear to be unlikely to initiate cancer in the absence of other driver events, such as Apc mutations in the case of the work by Smith et al.8, and might instead represent a more subtle contributing factor to tumorigenesis. By providing evidence that a combination of aging, somatic mtDNA mutations and perturbations in mitochondrial metabolism are important synergistic drivers of cancer development, the present work represents an important contribution to understanding the interplay of mitochondria, aging and cancer.
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The authors declare no competing interests.
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Prag, H.A., Murphy, M.P. mtDNA mutations help support cancer cells. Nat Cancer 1, 941–942 (2020). https://doi.org/10.1038/s43018-020-00128-x