**2.4. The surveillance of regulatory regions adjacent to the TSSs of human mitochondrial function-associated genes**

The surveillance of a human genomic DNA database suggested putative TPA-responsive elements in the 5′-upstream regions of the *MRPL32*, *NDUFB3*, *NDUFS3*, *SDHB*, and *SDHAF2* genes contain GGAA duplication [54]. The duplicated GGAA-motifs are present in the upstream regions of human genes encoding mitochondrial ribosomal proteins and enzymes or components that function in the TCA cycle and oxidative phosphorylation (OXPHOS) [54].

Mitochondrial dysfunction is thought to cause either cellular senescence or oncogenesis [55–58]. Remarkably, TCA cycle enzymes, fumarate hydratase (FH), and succinate dehydrogenase (SDH) have been suggested as tumor suppressors [59]. Hence, mutations of the TCA cycle factor-encoding genes give rise to abnormal mitochondrial respiration, which is one of the characteristics of tumors and cancer [60, 61]. Mutations of the *IDH1* and *IDH2* genes have been identified in human brain cancer cells [62, 63]. A recent study demonstrated that the mutation of IDH2 could lead to the generation of sarcoma [64]. Duplicated GGAA-motifs are contained in the upstream region of the *NAMPT* (*NmPRT*), encoding a nicotinamide phosphoribosyltransferase that catalyzes the first rate-limiting step of (nicotinamide adenine dinucleotides) NAD+ synthesis from nicotinamide [65–67]. Depending on the NAD+ level, NAMPT could modulate the TCA cycle, poly(ADP-ribosyl)ation, and sirtuin-mediated de-acetylation [66, 67]. The duplicated GGAA-motifs are present near the TSSs of the human TCA cycle enzyme-encoding *ACLY*, *ACO2*, *CS*, *FH*, *IDH1*, *IDH3A*, *IDH3B*, *SDHAF2*, *SDHB*, *SDHD*, and *SUCLG1* genes [68].

A duplicated GGAA-motif is present in the bidirectional promoter of the *PDHX* [54], which encodes one of the components of the PDH enzyme to metabolize pyruvate to acetyl-CoA. Aberrant pyruvate metabolism is thought to play a prominent role in cancer [69]. The genomic deletion of *ME2*, which encodes malic enzyme 2 (an NAD+ -dependent malate decarboxylase that converts malate into pyruvate), is found in pancreatic ductal adenocarcinoma [70]. The GGAA-duplication is not only found near the TSSs of the human *ME2* gene, but also the *MDH2* gene (which encodes NAD+ -dependent malate dehydrogenase), suggesting that duplicated GGAA-dependent transcription could affect the metabolism of malate in the mitochondria.
