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. Cert ain 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 th e 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 reg ulates only selected genes, even for subunits within the same complex and in widely varying species. By contrast, growth activation of quies cent NIH3T3 cells, a second paradigm used for stimulating mitochondria l biogenesis, does not increase cytochrome c(1) mRNA but does increase F-1-ATPase beta-subunit mRNA. These findings suggest that nuclear OXP HOS genes are not necessarily expressed in a coordinated manner, and t hat multiple regulatory circuits might exist which are linked to diffe rent physiological stimuli. Analysis of the promoters of several OXPHO S genes reveals a great diversity and heterogeneity of transfactor bin ding elements. No single regulatory feature exists which could account for a coordinated expression of all OXPHOS genes. The potential diver sity for regulating expression of nuclear OXPHOS genes raises the poss ibility for the existence of disease states linked to regulatory defec ts.