Thyroid hormone receptor isoforms localize to cardiac mitochondrial matrix with potential for binding to receptor elements on mtDNA

Thyroid hormone (T3) rapidly promotes both nuclear and mitochondrial DNA transcription in cardiomyocytes, suggesting that T3 directly binds and activates mitochondrial genes. We showed for the first time mitochondrial localization for multiple TRα isoforms in heart, including truncated versions. Additionally, we demonstrated novel mitochondrial localization for versions of TRα2, the dominant negative isoform lacking a functional ligand-binding domain. We also confirmed by electromobility shift assays, that TRα2 in mitochondrial extracts binds to thyroid receptor response elements present in the 12S rRNA (DRO) and D-loop region (DR2) of mitochondrial DNA. Thus, TRα isoforms may directly regulate T3 responses at mtDNA in the heart.