Mitochondrial genes as sites of primary action of steroid hormones

Steroid and thyroid hormones act on nuclear gene transcription by activating protein receptors, which in turn bind to hormone response elements (HREs). Among the cell-specific processes regulated by steroid receptors is energy metabolism through increased synthesis of respiratory enzymes. As some of these enzymes are encoded by both nuclear and mitochondrial genes, coordination of their synthesis is probable, inter alia at the transcrip- tional level. We have postulated a direct effect of steroid hormones on mitochondrial gene transcription and here present the following evidence in support of this hypothesis. 1) The human and rodent mitochondrial genomes contain nucleotide sequences similar both to type ! and type H HREs. 2) Glucocorticoid receptors (GR) rapidly translocate from the cytoplasm into mitochondria after administration of glucocorticoids. This process has been reproduced in vitro and deletion of the N-terminal part of the glucocorticoid receptor stops translocation into mitochondria. 3) Gel shift analysis has demonstrated binding of GR to putative mitochondrial GR elements. 4) In transfection experiments, mitochondrial HREs confer dexamethasone inducibility on hybrid reporter con- structs, abolished in the presence of excess RU38486. 5) Similar results were obtained for thyroid hormone receptor (TRy) localization, import, and binding to TR elements. These findings, taken with the demonstrated effects of steroid (and thyroid) hormones on mitochondrial transcription and respiratory enzyme biosynthesis, strongly support the hypothesis of a direct effect of steroid (and thyroid) hormones on mitochondrial gene transcription.