Fig. 3

Simplified scheme of T₃-dependent mitochondrial biogenesis through coordinated regulation of nuclear and mitochondrial gene products. T₃ binds to thyroid receptors (TRs) (1) which consecutively bind to response elements in the nucleus activating expression of mitochondrial-related genes such as PPARGC1A (2). Alternatively, specific TRs are localized in the mitochondrial matrix (p43). The T₃-p43 complex binds to response elements in the mitochondrial genome, of which two elements are located in the D-loop and one in the 12S rRNA (MT-RNR1) gene (3). We suggest that methylation of the mtDNA genome, in particular in the D-loop and MT-RNR1 region, could intervene with T₃-dependent mitochondrial protein production through conformational or structural changes making the mtDNA less accessible to proteins and transcription factors such as the T₃-dependent transcription factor p43 (4)