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Page 4 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 cell cycle . These studies determined that in budding yeast the metabolic cycle consists of three
[63]
phases : (1) oxidative respiration, marked by increased oxidative phosphorylation, increased ATP and
[64]
amino acid production. This phase is aligned with entry and progression into G1 of the cell cycle; (2)
reductive/building phase, characterized by an increase in glycolysis, increased production of nucleotides,
nucleosides and ethanol. This phase occurs in synchrony with S-phase and mitosis; (3) reductive/charging
characterized by production of complex carbohydrates for energy storage (e.g., glycogen, trehalose). This
phase occurs during the end of mitosis and entry into quiescence (G0). The synchronicity of the cell cycle
and metabolic cycle in budding yeast appears to be the result of a system of coupled oscillators, since the
metabolic cycle can continue to oscillate in the absence of cell division [65,66] . Intriguingly, the expression of
a number of cell cycle genes continues to oscillate with the metabolic cycle even in those cells that are not
undergoing cell division, suggesting that the metabolic cycle can regulate cyclic expression of cell cycle genes
independently of cell cycle controls .
[65]
Overall the evidence in budding yeast reveals an interaction between mitochondrial metabolism and the cell
cycle. Evidence of a similar interaction in other organisms has only recently started to emerge.

MITOCHONDRIA DYNAMICS ARE REGULATED BY THE CELL CYCLE
Early studies on the connection between mitochondria processes and the cell cycle in human cells
identified an increase in total mitochondria biomass that paralleled the increase in cell size during cell cycle
progression . The finding that mtDNA replication was not co-regulated with nuclear DNA replication , led
[68]
[67]
to the idea that mitochondria and cell cycle processes were mostly unlinked. This view has changed recently
as mounting evidence has shown that mitochondria biogenesis, morphology, dynamics and function are
regulated by the cell cycle.

Mitochondria are highly dynamic organelles undergoing constant fission and fusion. These dynamics depend
largely on several members of the dynamin family of proteins: mitofusin 1 and 2 (Mfn1/2) drive fusion of the
outer mitochondria membrane and optic atrophy protein 1 (Opa1) mediates inner mitochondria membrane
fusion, while dynamin-related protein 1 (Drp1) is required for mitochondria fission [69,70] . Mitochondria fission
is also facilitated by four receptors that cooperate to recruit Drp1 to the outer mitochondria membrane:
Mff, MiD49/51 and Fis1 [71,72] . Importantly, mitochondria morphology and dynamics change in a cell cycle-
dependent manner , with elongated mitochondria being dominant in G1 and short mitochondria being
[73]
[74]
dominant in mitosis . These changes in mitochondria dynamics during the cell cycle are controlled via
[75]
regulation of mitochondria-dynamics proteins by the cell cycle machinery [Figure 1].
Mitochondria fission during mitosis in human cells is driven by Drp1, whose activity is increased in mitosis
via phosphorylation by the mitotic cyclin Cyclin B1/Cdk1 . Drp1 phosphorylation in mitosis is promoted
[76]
by another mitotic kinase, Aurora A, via phosphorylation of the small GTPase RALA and its binding partner
RALBP1, which in turn bind to and facilitate Drp1 phosphorylation by Cyclin B1/Cdk1 . Mitochondria
[77]
fission in mitosis is important for mitochondria segregation. Depletion of RALA or RALBP1 result in
asymmetric segregation of the mitochondria to the two daughter cells, presence of mitochondria bridges
during cytokinesis, and in some cases cytokinesis failure due to interference of the indivisible mitochondria
mass with the cytokinetic ring . In turn, Drp1 promotes mitotic exit (adaptation) of cells arrested in mitosis
[77]
with the microtubule-stabilizing drug taxol via regulation of Cyclin B1 levels . Similarly, ATP depletion by
[78]
addition of 2-deoxy-glucose (2-DG) and sodium azide promotes mitotic exit in cells arrested in mitosis with
the microtubule depolymerizing drug nocodazole, and this adaptation is also due to reduction in Cyclin
B levels . These results indicate a bi-directional crosstalk where the mitotic machinery increases Drp1
[79]
activity and mitochondria dynamics in mitosis, which in turn feedbacks to regulate mitosis . Once the
[80]
cells exit mitosis, Drp1 is targeted for degradation by APC/C Cdh1[81] , shifting the balance of mitochondria
dynamics to favor mitochondria fusion.