In a recent paper in Nature Cancer, Smith et al. demonstrate that mitochondrial DNA
(mtDNA) mutations can confer a growth advantage to intestinal tumors by remodeling
cell metabolism, particularly toward elevated de novo serine synthesis.
1
For the reasons outlined below, in the past decade, the field of mtDNA biology has
experienced a relative loss of relevance. The findings of Smith et al. breathe welcome
new life into the complex field of mtDNA contributions to aging and cancer.
Compared to nuclear DNA (nDNA), mtDNA experiences high rates of mutation because it
is relatively unprotected, mtDNA repair mechanisms are far less sophisticated, and
mtDNA is located close to a major source of reactive oxygen species (ROS), the mitochondrial
electron transport chain. MtDNA mutations accumulate with age, and it was long thought
that they might contribute to the functional decline seen in aging. This idea was
dealt a lethal blow when a mouse accumulating mtDNA mutations at vastly increased
rates did not show accelerated aging.
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This decisive elimination of mtDNA from the pantheon of grand aging theories seemed
to leave no important role for accumulating mtDNA mutations in aging.
The dynamics of normal and mutant mtDNA are complex not only in intestinal carcinogenesis.
Cells usually contain hundreds of mtDNA molecules, each replicating according to metabolic
demand and independent of cell division. Damaged mtDNA molecules need to accumulate
and replace most normal mtDNA within a cell to cause mitochondrial efficiency to drop
significantly. Why this accumulation happens nonetheless is still poorly understood,
but might be driven in part by faster replication of truncated mtDNA and increased
mtDNA replication frequency induced by the energy crisis. On the level of cells, however,
it is clear that in the aging human intestine, cells harboring large amounts of mtDNA
mutations gradually expand and form patches of respiration-deficient cells. This clonal
expansion of respiration-deficient cells is, however, not observed in the mouse intestine,
and the lack of a good murine model is still hampering research. Smith et al. combine
mice homozygous for a proofreading-deficient polymerase γ (which accumulate very high
numbers of mtDNA mutations) with a model of intestinal tumorigenesis, tamoxifen-inducible
deletion of adenomatous polyposis coli in intestinal crypt stem cells. The difficulty
of replicating the human situation of expanding clones of respiration-deficient cells
is illustrated by the fact that they still resort to using homozygous polymerase γ
mutant mice, even though heterozygous mice also display expanding clones but no premature
aging phenotype.
Smith et al. nicely show that while the number of tumors was unaffected by the presence
of mtDNA mutations, mtDNA mutations increased tumor growth by inducing metabolic remodeling
towards anabolic growth. This hints at positive selection for mtDNA mutation-containing
cells and is supported by recently reported enrichment of mtDNA mutations not only
in colorectal but also in several other, notably kidney, cancer types.
3
The finding of altered one-carbon metabolism following respiratory chain disturbances
is not new.
4
Crucially, the same metabolic rewiring is also observed in many types of cancer, where
it is critical for growth and cell survival in the nutrient-starved environment of
a growing cancer.
It is my personal opinion that most of the many phenotypes that constitute aging are
nothing more than a consequence of tumor-suppressive mechanisms that had to evolve
to limit the danger posed by expanding clones of cells in large, long-lived organisms
like us. The tumor-suppressive mechanism is cellular senescence and irreversible growth
arrest. Smith et al. provide welcome new evidence that, in this view, not only oncogenic
nuclear DNA mutations contribute to cancer and aging, but, indirectly, also mtDNA
mutations. In this view, illustrated in Fig. 1, the clonal expansion of cells and
their tumorigenic potential, but not loss of any function or cell death, is, for the
organism as a whole, the only relevant consequence of somatic mutations in nDNA and
the mechanistic driver of aging. The beautiful results of Smith et al. show that the
same can be true for mtDNA mutations. At least in some organs, mtDNA mutations can
function as an oncogenic mutation by inducing metabolic remodeling, a bottleneck in
oncogenic transformation. In other organs, mtDNA mutations might have the opposite
effect, though.
3
Fig. 1
Cancer and aging as the dual consequences of somatic nDNA and mtDNA mutations. Oncogenic
and mtDNA mutations drive clonal expansion, which triggers tumor-suppressive cell
senescence but eventually leads to the characteristic loss of repair and regenerative
capacity in aging. What we experience as aging is simply, and mostly, the consequence
of a tumor-suppressive irreversible growth arrest that has evolved to limit the tumorigenic
potential of clonally expanding cells
So mtDNA mutations, by contributing to oncogenesis contribute to aging after all,
but only by driving oncogenesis. Cellular senescence suppresses cancer but causes
the aging phenotype (Fig. 1). A commentary on the results of ref.
2
was titled “Mitochondrial DNA mutations and aging: a case closed?” and stated that
“The conclusion seems inescapable that mtDNA point mutations are not causally related
to the aging process, at least in mice”. While this probably remains true for a direct
contribution towards any of the functional decline seen in aging, Smith et al.
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and Yuan et al.
3
firmly establish mtDNA contributions to tumorigenesis. Smith et al. also nicely show
that mtDNA mutations accelerate cell proliferation and reduce apoptosis,
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increasing the organismal burden of senescent cells. They also show that clonally
expanding but anatomically normal human colonic crypts upregulate serine synthesis
in response to mitochondrial deficiency.
1
This shows that mtDNA mutation-driven metabolic rewiring drives clonal expansion,
and therefore cellular senescence and aging, even in the absence of overt tumorigenesis.
So, after all, mtDNA mutations can still contribute to what we experience as aging.