**5.1. The mitochondria play the role of judge in the decision to induce cell death**

The execution of apoptosis is mediated by the mitochondria in response to various stresses, including DNA damage and immunological stress signals [138–140]. Thus, the mitochondria are known to serve as master regulators of danger signaling to determine cell death or survival [141]. Several mechanisms, including the regulation of the regulators of apoptosis [142, 143] and miRNAs [144], are involved in the induction of apoptosis. The surveillance of the human genomic DNA database indicated the presence of the duplicated GGAA-motifs in the 5′-regulatory regions of the human *PDCD1*, *DFFA*, *BCL2*, *FAS*, *FASL*, *ATG12/AP3S1*, *APOPT1/BAG5*, and *HTRA2/AUP1* genes [13, 53, 54]. These observations suggest that the expression of the apoptosis regulating factor-encoding genes is modulated by the GGAAduplicated sequences. In this context, apoptosis or programmed cell death, which is controlled by the mitochondria, partly depends on the GGAA-motif binding TFs.

adults, suggesting a relationship between DNA methylation and aging [123–125]. Moreover, the methylation and demethylation of the lysine residues of histones might affect the regulation of transcription [126]. In summary, AdoMet, a methyl group donor, plays an important

**4.3. The acetylation of histones could regulate the generation or progression of cancers**

proteins, including SIRT1 [116], which de-acetylate proteins, utilizing NAD+

of various genes, including the mitochondrial function-associated genes.

Acetyl-CoA is required for acetylation on the lysine residue of histones [127]. This process is catalyzed by acetyltransferases (HATs), including KAT2A (GCN5), KAT2B (CAF), KAT5 (ESA1), KAT7 (HBO1), and KAT8 (MOF) [128], which can be classified into two major groups: the GCNT and MYST families [129]. At least 11 enzymes are known to be histone deacetylases (HDACs) [130]. Because the increased or aberrant expression of HDACs has been reported in various cancers, inhibitors or modulators of HDACs are expected to be effective as anticancer drugs [131]. On the other hand, the lysine acetylation is negatively regulated by sirtuin

of the acetyl group [127]. It is hypothesized that a reduction in nutrient levels could induce

finding that CR mimetics prolong the life span [131–133]. In cancer cells, if mitochondrial dys-

TCA cycle, acetyl-CoA might only be converted to citrate to be used as an acetyl group donor for histones in the nuclei. If so, an increase in histone acetylation would occur naturally in the course of oncogenesis. The activation of HDACs in cancer cells might be the response to the aberrant hyper-acetylation of histone proteins that could lead to the abnormal transcription

histone acetylation directly or indirectly, and play essential roles in epigenetic control.

The mechanisms by which nuclear DNA damage signaling causes the mitochondrial dysfunctions that accelerate aging and aging-related diseases including cancer have been investigated in a review [134]. This process can be referred to as "mitonuclear communication" [135], suggesting that DNA repair systems are integrated into the mitochondrial functions. Given that α proteobacteria are the putative ancestors of the mitochondria [136], they need to take care of the nuclear DNAs that contain almost all (99%) of their essential protein-encoding genes [9]. Thus, the mitochondria might have developed a nuclear genome monitoring system, especially when DNA damage is induced. Several TCA cycles or metabolic enzymes functions as tumor suppressors [59, 64, 137], suggesting that mitochondrial dysfunction may lead to cancerous states.

**5. Mitonuclear communication regulates apoptosis, DNA repair,** 

**5.1. The mitochondria play the role of judge in the decision to induce cell death**

The execution of apoptosis is mediated by the mitochondria in response to various stresses, including DNA damage and immunological stress signals [138–140]. Thus, the mitochondria

to activate sirtuins. Histone de-acetylation is consistent with the

level or the hindrance of the progression of the

and acetyl-CoA could regulate DNA methylation and

as an acceptor

role in epigenetic control.

114 Mitochondrial Diseases

the accumulation of NAD+

**and aging**

function occurs with a reduction in the NAD+

To summarize, key metabolites, NAD+
