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Page 6 of 12 Herrera et al. J Cancer Metastasis Treat 2018;4:42 I http://dx.doi.org/10.20517/2394-4722.2018.35

of the DNA-damage kinases ATM and ATR . A similar G2 delay accompanied by DNA damage is also
[90]
observed after disruption of the Drp1 adaptor Fis1 . Disruption of other mitochondria functions, such as
[93]
in a Drosophila knockout of the mitochondria-specific form of RNaseZ and in human cells depleted of
[94]
mtDNA (rho0 cells) also cause a G2 delay. Furthermore the G2 delay after Fis1 depletion correlates with low
[95]
expression of the cell cycle transcription factor FoxM1 and its downstream mitotic genes, including Cyclin B1,
suggesting that defects in mitochondria dynamics/function can lead to transcriptional inhibition of the G2/M
transition . The link between mitochondria dynamics and cell cycle gene expression is further strengthened
[93]
by observations of a correlation between Drp1 expression levels and expression of cell cycle genes in different
cancers, particularly genes expressed in G2/M . Other metabolic alterations such as starvation and the
[96]
subsequent induction of autophagy, or hypoxia have also been shown to regulate cell cycle progression .
[97]
Mitochondria dynamics/function have a role in the regulation of mitosis since Drp1 activity and ATP
depletion promote mitotic exit in cells arrested in mitosis with microtubule-targeting drugs [78,79] . This exit
from mitotic arrest when mitochondria function is compromised is due to premature degradation of Cyclin
B1 by activation of the ubiquitin ligase APC/C Cdh1[79] . These results indicate a complex cross-talk between
mitochondria functions and the mitotic machinery, which has important implications for our understanding
of the response of cancer cells to microtubule-targeting agents commonly used as cancer treatments (e.g., taxol,
vinblastine). Additionally, other mitotic phenotypes are observed in cells with compromised mitochondria
[98]
function, including amplification of centrosomes [90,95] , abnormal centrosome positioning , chromosome
misalignment and multipolar spindles . However, whether these phenotypes indicate a role for the
[90]
[95]
mitochondria in the regulation of centrosome duplication or mitosis, or are merely consequences of the G2
delay and DNA damage observed in these cells has not been elucidated. Paradoxically, incubation with the
Drp1 inhibitor Mdivi-1 seems to exert the opposite effect in cells damaged by x-rays. X-ray irradiation results
in DNA damage, abnormal progression through mitosis (mitotic catastrophe), centrosome amplification
and formation of micronuclei. In this scenario, incubation with the Drp1 inhibitor Mdivi-1 reduced the
centrosome amplification and formation of micronuclei observed after irradiation .
[99]
Taken together, these results provide clear evidence of a bidirectional link between mitochondria dynamics/
function and cell cycle progression at multiple phases. However, more research is needed to fully understand the
extent of interaction between these processes and to understand the molecular underpinnings of this crosstalk.

OTHER LINKS BETWEEN THE MITOCHONDRIA AND NUCLEAR FUNCTION
As discussed previously, one of the best studied endogenous sources of genomic instability is the mutagenic
potential of ROS, which can induce oxidative DNA damage [35,36] . Increased levels of ROS have also been
shown to induce other types of damage such as telomere attrition and chromosome fusions . However,
[100]
other mechanisms by which mitochondrial dysfunction affects nuclear genome instability have started to
emerge [Figure 2]. In budding yeast, loss of mtDNA leads to genomic instability and this was not correlated
with defects in respiration, but rather with defects on the mitochondrial processing of iron-sulfur clusters .
[101]
In addition, mtDNA can affect nuclear DNA through direct transfer of genes. This process, termed
numtogenesis , was thought to be a rare event occurring at an evolutionary scale of millions of years.
[102]
However, several reports have identified higher rates of numtogenesis in cancer cells. For example, a study
identified mtDNA in the nuclei of up to 27.5% of cervical carcinoma cells compared to 0% of paired cells
from the normal cervical epithelium . Increased rates of numtogenesis were also observed via analysis of
[103]
whole genome sequencing of adenocarcinoma samples . Importantly, mtDNA integration into the nuclear
[104]
genome can have important consequences such as activation of oncogenes .
[105]
Another direct link between the mitochondria and genomic instability has been observed in cells that survive
exposure to pro-apoptotic stimuli. Exposure of cells to a sub-lethal dose of the BH3-mimetic ABT737 results