**4. Interaction of mitochondria and epigenetics in HCC: An overview**

The epigenome can be altered not only by environmental factors, such as exposure to exogenous chemicals [63] but also by changes in the levels of endogenous cofactors and metabolites [64, 65]. The exact correlation between nucleus and mitochondrion allows for the maintenance of mitochondrial structure and function. On the one hand, the nuclear gene expression is regulated by mitochondrial intermediates, like acetyl-CoA, ATP, NAD+ , and s-adenosylmethionine, which are the link between the epigenome and calorie availability [47, 66]. In addition to the production of epigenetic substrates, mitochondria may be modified in their DNA (mtDNA). Some mitochondrial genes have been reported as hypermethylated in HCC; for example, mitochondrial ribosomal protein S12 (*Mrps12*), mitochondria-localized glutamic acid-rich protein *(Mgrap*), and transmembrane protein 70 (*Tmem70*) genes [67, 68]. On the other hand, the disruption of the step in the methylation of 5-mC to 5-hmC in the mitochondrial genome leads to the alteration of several OXPHOS genes, such as: NADH dehydrogenase (ubiquinone) 1 subunit C2 (NDUFC2), NADH dehydrogenase (ubiquinone) flavoprotein 1 (NDUFV1), NADH: ubiquinone oxidoreductase subunit S6 (NDUFS6) from complex 1. These modifications, added to the mitochondrial damage by oxidative stress, can favor the loss of ETC function. In addition to that, it has been reported that the mitochondrial genome damage can affect the expression of nuclear genes [69–71]. Moreover, there is a deregulation of hepatic one carbon, and TCA cycle, therefore it driving the aberrant epigenetics changes [72–74]. The main consequence of depressing the TCA cycle is the reduced availability of α-ketoglutarate, leading to a decrease in the activity of α-ketoglutarate-dependent proteins, which are responsible for the hydroxylation of many substrates in the cell that are important in epigenomic control [74].

Tumor cell metabolism can be linked to epigenetic changes during carcinogenesis; recent research has focused on epigenetic studies in relation to metabolic pathways [75, 76]. HCC is a heterogeneous disease affected by various lifestyles and environmental factors. Epigenetic alterations are frequently caused by these factors and contribute to hepatocarcinogenesis. During HCC development, different alterations in global DNA methylation have been described; for example, global hypomethylation leads to aberrant overexpression of oncogenes and large chromosomal instability [77, 78].

In cirrhosis and HCC, distinct patterns of aberrant DNA methylation associated with cirrhosis and HCC have been confirmed [79, 80].
