Figure 1: Dysfunction of tricarboxylic acid (TCA) cycle, which could be caused by attenuation of GGAA-dependent transcription. Duplicated GGAA-motifs are contained in the 5’-upstream regions of the ACO2, GLUD2, IDH1, IDH3A, IDH3B, MDH2, ME2, SUCLG1, SDHAF2/SDHB/SDHD, FH, ACLY, CS, and PDHX genes. Various cellular stresses, including chemicals, X-ray and UV irradiation, virus infection, and aging, may alter the transcriptional state leading to disruption of the mitochondrial function- and DNA repair-associated gene expression. Damage on DNAs activate PARP enzyme, which consumes NAD+ molecule to synthesize poly(ADPribose), may further lead to dysfunction of the TCA-cycle. Thus cells must depend on glycolysis to synthesize ATP. The consequence could be referred to as the “Warburg effect”. This hypothesis implies that pre-cancerous state could be prevented if NAD+/NADH ratio were ameliorated.