THE ROLE OF THYROID-HORMONE AND PROMOTER DIVERSITY IN THE REGULATION OF NUCLEAR-ENCODED MITOCHONDRIAL PROTEINS

Thyroid hormone regulates the in vivo expression of a selected set of rat nuclear genes encoding mitochondrial inner membrane proteins. Certain mRNAs, such as that for cytochrome c(1), are increased as much as 20-50-fold, while others, such as core protein 1 of Complex III and the F-1-ATPase beta-subunit do not respond. The promoter region of human cytochrome c(1) also supports thyroid hormone induction of a reporter gene in transient transfection experiments. Thus, thyroid hormone regulates only selected genes, even for subunits within the same complex and in widely varying species. By contrast, growth activation of quiescent NIH3T3 cells, a second paradigm used for stimulating mitochondrial biogenesis, does not increase cytochrome c(1) mRNA but does increase F-1-ATPase beta-subunit mRNA. These findings suggest that nuclear OXPHOS genes are not necessarily expressed in a coordinated manner, and that multiple regulatory circuits might exist which are linked to different physiological stimuli. Analysis of the promoters of several OXPHOS genes reveals a great diversity and heterogeneity of transfactor binding elements. No single regulatory feature exists which could account for a coordinated expression of all OXPHOS genes. The potential diversity for regulating expression of nuclear OXPHOS genes raises the possibility for the existence of disease states linked to regulatory defects.