We have recently demonstrated that mitochondrial respiratory dysfunction and mitochondrial permeability transition (MPT) pore opening during postinfarction remodeling are prevented by the Na⁺-H⁺ exchange-1 (NHE-1)-specific inhibitor EMD-87580 (EMD). One of the mechanisms underlying the beneficial effect of NHE-1 inhibition on mitochondria could result from the drug's ability to regulate transcriptional factors responsible for mitochondrial function. In the present study the effect of EMD on the expression of nuclear factors involved in mitochondrial biogenesis as well as expression of nuclear (COXNUCSUB IV) and mitochondrial (COXMITSUB I) encoded cytochrome c oxidase subunits has been studied in rat hearts subjected to either 12 or 18 weeks of coronary artery ligation (CAL). Remodeling induced an increase in expression of the hypertrophic marker gene ANP, especially 12 weeks after CAL. The mRNA level of the peroxisome proliferators activated receptor gamma co-activator 1 (PGC-1) and its downstream factors including nuclear respiratory factor 1 (NRF-1) and 2 (NRF-2), mitochondrial transcription factor A (MTF A), COXNUCSUB IV and COXMITSUB I were significantly reduced in hearts both 12 and 18 weeks following ligation compared to sham-operated hearts. Dietary EMD provided immediately after ligation attenuated downregulation of mitochondrial transcription factors with a parallel decrease of hypertrophic marker gene expression. Regression analysis demonstrated a strong positive correlation between the transcription factors and mitochondrial respiratory function. Thus, our study shows that the downregulation of mitochondrial transcription factors induced by postinfarction remodeling can be significantly attenuated by NHE-1 inhibition with a further improvement of mitochondrial function in these hearts.