Mitochondrial Control of Genomic Instability in Cancer

Simple Summary Cancer cells display among its hallmark genomic instability. This is a progressive tendency in accumulate genome alteration which contributes to the damage of genes regulating cell division and tumor suppression. Genomic instability favors the appearance of survival-promoting mutations, increasing the likelihood that those mutations will propagate into daughter cells and have a significant impact on cancer progression. Among the many factor influencing this phenomenon, mitochondrial physiology is emerging. Mitochondria are bound to genomic instability by responding to DNA alteration to trigger cell death programs and as a source for DNA damage. Mitochondrial alterations prototypical of cancer can desensitize the mitochondrial route of cell death, facilitating the survival of cell acquiring new mutations, or can stimulate mitochondrial mediated DNA damage, boosting the mutation rate and genomic instability itself. Abstract Mitochondria are well known to participate in multiple aspects of tumor formation and progression. They indeed can alter the susceptibility of cells to engage regulated cell death, regulate pro-survival signal transduction pathways and confer metabolic plasticity that adapts to specific tumor cell demands. Interestingly, a relatively poorly explored aspect of mitochondria in neoplastic disease is their contribution to the characteristic genomic instability that underlies the evolution of the disease. In this review, we summarize the known mechanisms by which mitochondrial alterations in cancer tolerate and support the accumulation of DNA mutations which leads to genomic instability. We describe recent studies elucidating mitochondrial responses to DNA damage as well as the direct contribution of mitochondria to favor the accumulation of DNA alterations.