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Figure 2. Mitochondria functions impact nuclear functions. Model showing the different aspects of mitochondria function that have been
shown to affect the nuclear genome at the level of gene expression (e.g., via calcium signaling pathways), genomic instability (e.g., DNA
damage, telomere attrition) or epigenetic modifications (e.g., DNA methylation, histone modifications)

in partial mitochondria outer membrane permeabilization (MOMP), partial caspase activation and increased
[106]
DNA damage . One of the mitochondrial proteins, released from the mitochondria during MOMP is
apoptosis inducing factor (AIF). AIF translocates to the nucleus and binds to the nuclear DNA, triggering
condensation and fragmentation [107-109] . Importantly this nuclear translocation of AIF has also been observed
in cells exposed to sublethal doses of oxidative stress , suggesting that release of mitochondrial proteins
[110]
like AIF can result in DNA damage without triggering apoptosis.

In addition to introducing genomic instability, the mitochondria also modulates nuclear functions via
retrograde signaling that regulates nuclear gene expression. Mitochondria play a role in the epigenetic
regulation of the nuclear genome [111,112] . DNA methylation patterns have been shown to change in cells
depleted of mtDNA (rho0) and in cells with different mtDNA haplotypes . Mitochondria also have a role
[114]
[113]
in calcium regulation, and mitochondrial stress can induce calcium release, activating signaling cascades
that can lead to different nuclear gene expression responses and phenotypic changes, such as increases in
invasive behavior . Similarly, reduction in mtDNA content in breast cancer cells activates a calcineurin-
[115]
dependent pathway that induces phenotypic changes similar to the epithelial-to-mesenchymal transition
(EMT) associated with higher cancer aggressiveness . Retrograde signaling, alteration of epigenetic
[116]
regulation, direct transfer of genetic material, and ROS-mediated effects demonstrate the myriad of ways
that mitochondrial dysfunction can play a role in nuclear genome instability and function.

IMPLICATIONS OF MITOCHONDRIA-NUCLEAR INTERACTIONS FOR CANCER
Deregulation of cellular energetics is considered one of the emerging hallmarks of tumor development, while
genomic instability has been established as an enabling characteristic of cancers . The results discussed
[117]
in this review provide evidence for a complex bidirectional cross-talk between mitochondria processes and
nuclear processes involved in genomic maintenance, particularly regulation of the cell cycle. Identifying
the molecular players involved in this cross-talk will not only open possibilities for the development of new
cancer treatments, but it also reveals an unexpected complexity where genomic instability and defects in
mitochondria function can synergize to accelerate cancer progression. That is, as cancer progresses and
cell metabolism changes, these changes could lead to modifications in cell proliferation due to cell cycle
dysregulation; while in turn modifications in the cell cycle or genomic instability can induce changes in
mitochondria function, leading to a synergistic acceleration in the acquisition of cancer-associated traits.