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Lozano-Rosas et al. Hepatoma Res 2018;4:19 I http://dx.doi.org/10.20517/2394-5079.2018.48 Page 3 of 14

Glucose is the main source of Ac-CoA and is the link between glycolysis and the tricarboxylic acid cycle
(TCA). In addition to its energetic role, the Ac-CoA is the substrate for acetylation reactions that are
important to modulate gene expression and the function of some proteins . Acetylation of mitochondrial
[21]
substrates is controlled by a NAD -dependent deacetylase sirtuin-3 (Sirt-3). Therefore, the mitochondrial
+
+
redox state must be controlled to maintain the NAD availability for the Sirt-3 activity.
On the other hand, SAM is the physiological methyl donor group synthesized from L-methionine and ATP
in a reaction catalyzed by the methionine adenosyltransferase (MAT) enzyme . SAM is synthesized in the
[22]
cytosol and imported to the mitochondrial matrix via the mitochondrial SAM carrier, likely via exchange
for its metabolized variant S-adenosyl-homocysteine (SAH) . SAM synthesis is regulated in part by the
[23]
mitochondrial one-carbon (folate) metabolism . An enzyme that participates in mitochondrial folate
[24]
metabolism, the mitochondrial bifunctional enzyme (MBE), regulates the change between SAM and the
nucleotide synthesis. In proliferative cells, such as embryonic or cancer cells, MBE is expressed, and the
one-carbon units are shuttled predominantly towards nucleotide synthesis. Under these conditions, less
one-carbon units are available for SAM synthesis and DNA methylation. Conversely, in differentiated cells,
MBE is turned off, less mitochondria toward nucleotides synthesis are produced, and one-carbon units are
directed through increased SAM synthesis and increased DNA methylation . SAM is important for DNA
[25]
epigenetic, methylation of phospholipids , and proteins; thus, modulating relevant cellular functions. For
[26]
example, the relationship between methylation and mitochondrial dysfunction being so close that deficiency
of SAM may lead to mitochondrial damage and, finally, to insulin resistance .
[27]

PRINCIPAL MITOEPIGENETICS PROCESSES
mtDNA methylation and hydroxymethylation
DNA methylation is an epigenetic modification of the DNA that is frequently disrupted in nearly all types of
cancer. Hypomethylation of the repetitive elements associated with increased genomic instability is frequently
observed in cancer cells . The hypermethylation of specific CpG islands in promoter regions of several
[28]
tumor-suppressor genes is commonly observed to be associated with transcriptional silencing of the gene [29,30] .
Epigenetic regulation of the mitochondrial genome was an enigma, until recent studies . For example,
[31]
there is no evidence of post-translational modifications of TFAM as it happens in nuclear DNA histones,
and the most important epigenetic regulation of mtDNA is DNA methylation and hydroxymethylation. DNA
methylation is regulated by four DNA methyltransferases (DNMT1, 3A, 3B, and 3L) and three demethylases,
that is, ten-eleven translocations (TET1-3) .
[32]

The mtDNA methylation is accomplished by the mitochondrial DNA methyltransferase (mtDNMT1),
a nuclear encoded DNMT1 that contains a mitochondrial targeting sequence . Methylation of nDNA
[33]
occurs principally in cytosines (5mC) of CpG dinucleotides, but recently it has been shown that mtDNA
methylation is found predominantly in non-CpG sites and that it is DNMT independent . In general,
[4]
mtDNA is undermethylated, with only 1% to 5% of methylated cytosines. Several factors increase mtDNMT1
transcription and translocation to the mitochondria, like p53, oxidative stress-responding transcription
factors, nuclear respiratory factor 1 (NRF1), peroxisome proliferator-activated receptor gamma coactivator
[33]
1-α (PGC-1α), and p16 cell cycle inhibitor . The methyltransferase DNMT3a may also be involved in the
methylation of mtDNA since it has been found in mitochondrial fractions from mouse cell lines and from the
[32]
human central nervous system . In 2011, Shock et al. reported the presence of 5-hydroxymethylcytosine
[33]
(5hmC) and 5-methylcytosine (5mC) in mammalian mtDNA, further demonstrating the translocation
of methyltransferase 1 (DNMT1) to mitochondria. Alterations in mtDNMT expression affect transcripts
of the heavy and light strands of mtDNA. The modulation of mtDNA methylation has been studied in
response to oxidative stress, where there seems to be a decrease in this modulation , this response can be
[34]
a compensatory response to mtDNA damage by increasing the expression of residual mtDNA genes. The