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its origin is nuclear it can be exported to the mitochondria and execute its effect [46,47] . In addition, miR-499
regulates mitochondrial dynamics through mitochondrial fission protein and apoptosis .
[48]

Epigenetic regulation of nuclear-encoded mitochondrial genes
Mitoepigenetics includes the regulation of nuclear-encoded mitochondrial genes as previously mentioned in
its definition; importantly, two of the transcription factors that carried out this modulation are: PGC-1α and
NRF-1. However, as we describe in this section, little is known about its epigenetic regulation in HCC, then,
it represents an area of study to explore.

PGC-1α
PGC-1α is critical for the expression of genes involved in fatty acid oxidation, as well as in mitochondrial
gene expression through the coactivation of major transcription factors, controlling the complex program of
mitochondrial biogenesis . It has been suggested that biogenesis induced by PGC-1α is tumor promoting .
[49]
[50]
Sirtuin-1 (Sirt-1), a NAD -dependent deacetylase, targets several transcription factors, like PGC-1α, both
+
proteins have been found overexpressed in HCC and are related to defective mitochondrial accumulation .
[51]
Non-CpG methylation of the PGC-1α promoter controls mitochondrial density and has been detected in
pathological conditions such as obesity . It may be interesting to obtain an epigenetic PGC-1α pattern in
[52]
HCC to know if its modulation is carcinogenesis stage-dependent and to establish the accurate way to be
pharmacologically controlled.
NRF-1
NRF-1 binds to the cytochrome C promoter and positively regulates nuclear-encoded mitochondrial genes ;
[53]
low-levels of NRF-1 cause mitochondrial dysfunction. The NRF-1 gene sequence has several CpG islands
which are susceptible to methylation and demethylation processes; it has been shown that hypermethylation
of the promoter region of NRF-1 causes a decrease in its expression . Further studies of the epigenetic
[54]
regulation of NRF-1 in HCC are needed.

MITOEPIGENETICS IN HCC
One of the most and consistent phenotypes of cancer are defective mitochondria. There is evidence that
the loss of mitochondrial function and epigenetic alterations in this organelle are related to the process
of carcinogenesis because of their vital role in energy production and contribution to the metabolism of
epigenome effectors [1,55,56] . Mitochondrial dysfunctions also lead to resistance to apoptosis. Since Warburg's
hypothesis, a number of mitochondrial abnormalities in cancers, both at the genetic and metabolic levels,
have been reported [8,9,11] .

Moreover, progressive mitochondrial dysfunction has been linked to an enormous variety of diseases, such
as mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome (MELAS), Leber’s
hereditary optic neuropathy (LHON), deafness, diabetes, Alzheimer, and Parkinson disease [57,58] .

Alterations observed in the epigenetic substrates in HCC
As previously reported, metabolic alterations have been found in liver diseases and the HCC is not
[6,7]
the exception; the metabolic reprogramming that happens in cancer cells implies a decrease in ATP [8,59] .
However, some studies have not found significant changes in acetyl-CoA levels that normally depend on
energy metabolism, but which, in HCC, may have a nuclear origin and play a fundamental role in the
progression of the cell cycle and DNA replication [8,60] .

We have mentioned that the mitochondrial redox state is fundamental for the proper functioning of
mitochondria; with respect to HCC, it is known that the NAD /NADH ratio decreases significantly , which
+
[8]
could modify the activity of enzymes that depend on the cellular redox state. On the other hand, currently a