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Page 2 of 14 Lozano-Rosas et al. Hepatoma Res 2018;4:19 I http://dx.doi.org/10.20517/2394-5079.2018.48

Mitoepigenetics events include the interplay between mitochondrial-derived substrates and the nuclear
epigenetic landscape. This includes all epigenetic events that affect the expression of the mitochondrial
genome and the nuclear-encoded mitochondrial genes . The importance of mitoepigenetics lies not only in
[3,4]
the functions described for this organelle, but also in the generation of intermediaries that serve to regulate
the function of other cellular components, as will be mentioned later.

Mitochondrial dysfunction is involved in several diseases including cancer . The ability of mitochondria
[5]
to regulate the energetic redox state and the metabolism of cells could result in the production of epigenetic
intermediates that participate in normalization of the mitochondrial function. Studies have revealed several
metabolic alterations in liver diseases including modification in energy supply . A sequential model of
[6,7]
cirrhosis-HCC induced by diethylnitrosamine (DEN) revealed that cancer progression is associated with
mitochondrial dysfunction .
[8]

Multiple insults to the mitochondrial genome have been associated with different pathophysiologies, and
have been described as one of the most common and consistent phenotypes of cancers [9-13] .

Mitochondria are vital for the cell because they are responsible for its metabolic activity, as well as for
producing the bulk of the energy requirements in the form of ATP, maintaining calcium homeostasis, and
inducing apoptosis [14,15] . In mitochondria, ATP is generated through the process of oxidative phosphorylation
(OXPHOS), which occurs via the electron transport chain (ETC). Mitochondria contain their own genome
(mitochondrial DNA, mtDNA). Each organelle contains about 1-10 copies of mtDNA . MtDNA is distinctly
[16]
different from the nuclear DNA (nDNA), the mtDNA is a circular, double-stranded DNA molecule of
approximately 16.6 kb in size and it is inherited only through the mother. MtDNA is found associated and
packed with proteins in a nucleoid, where an encoded nuclear protein known as mitochondrial transcription
factor A (TFAM) is the major protein component . The mtDNA comprises a heavy (H) strand and a light
[17]
(L) strand, which encode 13 of the polypeptides that constitute the complexes I, III, IV, and V of the ETC.
MtDNA also encodes some of its own transcriptional and translational machinery, which includes 22 tRNAs
and 2 rRNAs [12,13,18] . The rest of the mitochondrial proteins (~1500), involved in the mitochondrial function,
replication, transcription and translation of mtDNA, are encoded by nuclear genes and are targeted to the
mitochondrion by a specific transport system .
[19]

METHODS
A bibliographic search was performed of the Medline database (US National Library of Medicine, http://
www.ncbi.nlm.nih.gov). The keywords used or combinations of them were: cancer, hepatocellular
carcinoma, epigenetics, mitoepigenetics, mitochondria, methylation, hydroxymethylation and miRNA. All
the articles that included the terms and/or combinations referring to the metabolic regulation, as well as to
mitoepigenetics in HCC were selected.

EPIGENOME SUBSTRATES GENERATED BY MITOCHONDRIA
Cellular growth and replication depends on the energetic state through epigenetic modifications in the DNA
chromatin structure . This is achieved by coupling modulation of nDNA chromatin structure and function
[20]
by modification via high energy intermediates: phosphorylation by ATP, acetylation by acetyl-coenzyme A
+
(Ac-CoA), deacetylation by nicotinamide adenine dinucleotide (NAD ), and methylation by S-adenosyl-
methionine (SAM) . As afore mentioned, the mitochondrion is responsible for ATP production as part of
[20]
the energetic metabolism. However, the role of ATP is not just to be the main energy provider, but it also
regulates multiple cellular functions through phosphorylation and dephosphorylation reactions (when there
are low levels of ATP), as part of what is known as post-translational modifications.