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Aims Sarco(endo)plasmic reticulum Ca2+-ATPase 2a (SERCA2a) transports Ca2+ by consuming ATP produced by mitochondrial respiratory chain enzymes. Messenger RNA (mRNA) for these enzymes is transcribed by mitochondrial transcription factors A (TFAM) and B2 (TFB2M). This study examined whether TFAM and TFB2M coordinately regulate the transcription of the Serca2 gene and mitochondrial genes. Methods and results Nuclear localization of TFAM and TFB2M was demonstrated by immunostaining in rat neonatal cardiac myocytes. Chromatin immunoprecipitation assay and fluorescence correlation spectroscopy revealed that TFAM and TFB2M bind to the −122 to −114 nt and −122 to −117 nt regions of the rat Serca2 gene promoter, respectively. Mutation of these sites resulted in decreased Serca2 gene transcription. In a rat myocardial infarction model, Serca2a mRNA levels significantly correlated with those of Tfam (r = 0.54, P < 0.001) and Tfb2m (r = 0.73, P < 0.001). Overexpression of TFAM and TFB2M blocked hydrogen peroxide- and norepinephrine-induced decreases in Serca2a mRNA levels. In addition, overexpression of TFAM and TFB2M increased the mitochondrial DNA (mtDNA) copy number and mRNA levels of mitochondrial enzymes. Conclusion Although TFAM and TFB2M are recognized as mtDNA-specific transcription factors, they also regulate transcription of nuclear DNA, i.e. the Serca2 gene. Our findings suggest a novel paradigm in which the transcription of genes for mitochondrial enzymes that produce ATP and the gene for SERCA2a that consumes ATP is coordinately regulated by the same transcription factors. This mechanism may contribute to maintaining proper cardiac function. [ABSTRACT FROM AUTHOR]