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Herrera et al. J Cancer Metastasis Treat 2018;4:42 I http://dx.doi.org/10.20517/2394-4722.2018.35 Page 5 of 12

Figure 1. Crosstalk between mitochondria dynamics and the cell cycle. Model showing the changes in mitochondria dynamics and Drp1 activity
throughout the cell cycle. Mitochondria fusion is favored in G1 and mitochondria fission is dominant in mitosis. This leads to the formation
of a highly elongated and interconnected network during late G1, and small disconnected mitochondria in mitosis. Changes in mitochondria
dynamics are regulated by the cell cycle machinery, for example mitochondria fission is favored in mitosis by Drp1 phosphorylation by the
mitotic kinase Cyclin B1/Cdk1. Conversely, mitochondria fusion is favored in G1 due, at least in part, to degradation of Drp1 by the ubiquitin
ligase APC/C-Cdh1 in early G1. In turn, these changes in mitochondria morphology regulate the cell cycle. Hyperfused mitochondria
promote the G1/S transition, while inhibition of Drp1 induces a G2 arrest and failure to fragment mitochondria in mitosis can interfere
with cytokinesis. These phenotypes have started to reveal a profound level of cross-talk between these two processes

In addition to regulating mitochondria dynamics, cell cycle proteins also regulate respiration and other
mitochondrial processes. Cyclin D1 represses mitochondria function by inhibiting nuclear respiratory factor 1
[82]
(NRF1), a transcription factor that induces expression of a set of nuclear-encoded mitochondrial genes ,
and regulates gluconeogenesis . A pool of Cyclin B1/Cdk1 localizes to the mitochondria, phosphorylates
[83]
[84]
components of the OXPHOS machinery and increases their activity at the G2/M transition . Some
components of the spindle assembly checkpoint (e.g., Mad2, BubR1, p31-comet) have roles in insulin
signaling , while others (e.g., Mps1, Survivin) localize to the mitochondria and regulate apoptosis [86,87] .
[85]
Together, these results indicate extensive regulation of mitochondria functions and/or cell metabolism by
the cell cycle machinery.

THE CELL CYCLE IS IN TURN REGULATED BY MITOCHONDRIA FUNCTION
Increased mitochondria fusion after mitotic exit leads to the formation of a hyperfused mitochondria
network in late G1 which promotes the transition from G1 into S-phase . The molecular mechanism by
[74]
which mitochondria hyperfusion promotes S-phase entry has not been completely elucidated. However,
it appears that mitochondria hyperfusion and the accompanying increase in mitochondria respiration in
late G1 promotes accumulation of the S-phase cyclin, Cyclin E . Conversely, inhibition of respiration in
[74]
G1 using the uncouplers FCCP or CCCP results in decreased Cyclin E accumulation and delay in S-phase
entry [74,88] . This model is supported by an analysis of mitochondrial potential (ΔΨm) in a population of G1
cells which showed that G1 cells with low ΔΨm have a molecular profile corresponding to early G1 cells (e.g.,
low Cyclin E, high p27Kip1), while G1 cells with high ΔΨm have a late G1 molecular signature (e.g., high
Cyclin E, low p27Kip1) .
[89]
In addition to its role in promoting the G1/S transition, mitochondria dynamics also regulate the G2/M
transition. Depletion of Drp1 results in a G2 arrest [90-92] , due to the presence of DNA damage and activation