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tumors [46,47] , with 31.1% of the tumors harboring multiple mtDNA mutations . Unlike the nuclear genome,
[47]
which contains two alleles of each gene, the mtDNA complement of a cell consists of hundreds to thousands
of circular mtDNA molecules, allowing for different layers of mtDNA heterogeneity: alterations in mtDNA
copy number, mutations in the mtDNA that occur in some but not all copies of the mtDNA genome within
a cell (heteroplasmy), or mutations in the mtDNA that show dominance and accumulate until the mutant
mtDNA becomes the only version present in the cell (homeoplasmy). Differences in mtDNA copy number,
both increases and decreases of mtDNA relative to normal tissue, have been observed in many cancer types
with some studies showing mtDNA copy number variation in up to 88% of tumors . However, the role
[48]
of mtDNA mutations or copy number variations as potential causative agents in cancer development have
not been fully established due to the technological difficulties of manipulating the mtDNA genome. Studies
in mice that have mtDNA from one strain and nuclear DNA from another strain (i.e., mice generated by
mitochondrial-nuclear exchange) show effects in cancer progression models including changes in tumor size
and metastatic burden , suggesting that the mtDNA can affect cancer progression.
[49]

INTERPLAY BETWEEN MITOCHONDRIA AND NUCLEAR FUNCTIONS
Genetic interconnections between the nucleus and the mitochondria are evident, since all but thirteen
mitochondrial proteins are encoded by the nuclear genome. Associations between nuclear-encoded mitochondrial
genes and tumorigenesis have been found, including mutations in several subunits of complex II, succinate
dehydrogenase and isocitrate dehydrogenase, among other mitochondrial enzymes [50,51] . This nuclear
control of the mitochondria by regulation of nuclear-encoded mitochondrial genes is termed anterograde
signaling, and it is complemented by an equally important retrograde signaling system that allows the
mitochondria to relay signals to the nucleus [52,53] . Retrograde signaling was first identified via changes
observed in transcription of nuclear genes in response to respiration defects . Later studies established
[54]
that the retrograde signaling response is a mitochondria quality control mechanism in which the cell senses
different mitochondrial functions (e.g., ROS production, the TCA cycle, calcium levels, the unfolded protein
response), and communicates the status of these functions to the nucleus via signaling cascades [52,53] . These
retrograde signals activate diverse nuclear responses, setting in motion multiple pathways that regulate
energy homeostasis, oxidative stress, and mitophagy, among other functions [52,53,55] .

Importantly, mitochondria-dependent regulation of other nucleo-centric processes has started to emerge,
including a role in regulation of the cell cycle.

THE MITOCHONDRIA MEETS THE CELL CYCLE
The eukaryotic cell cycle consists of four phases G1, S-phase, G2 and mitosis. These phases were historically
defined by two genome-centric processes: DNA duplication (S-phase) and chromosome segregation (mitosis),
interspersed with “gap” phases (G1 and G2) to allow for cell growth . It is now understood that the cell
[56]
cycle involves more than duplication and segregation of DNA. During a cell cycle cells must also grow and
segregate their organelles and other cellular structures [57-59] . This duplication of the genome and increase
in cell biomass, followed by the complex division of all cell contents to form two fully functional daughter
cells requires a large amount of energy and metabolites. Links between metabolism and the cell cycle were
identified early in the history of cell cycle research via genetic screens in budding yeast that identified Cell
Division Cycle (CDC) mutants . Several of the original CDC alleles, which cause cell cycle defects when
[60]
grown at the non-permissive temperature, were later discovered to also result in reduced carbon metabolism
and lower ATP production . Conversely, mutations in cell cycle genes, such as the cyclin-dependent kinase
[61]
CDC28 were found to also affect mitochondria biogenesis .
[62]
This metabolism-cell cycle connection has been studied in detail in budding yeast. Analysis of synchronously
growing yeast populations uncovered cyclic changes of metabolism that associate closely with the phases