Role of transcription factors in mtDNA biogenesis mediated by thyroid hormones

Abstract

Exogenous thyroid hormones are regulators of cellular metabolism that involves, along with other cell structures, mitochondria. Mechanisms of the influence of thyroid hormones on the biogenesis of mtDNA are not fully understood due to their pleiotropic nature. Different ways of regulation of mitochondrial biogenesis by thyroid hormones are discussed in literature, but thyroid receptors, localized in both the nucleus and mitochondria, are the main elements of most pathways. Data on events occurring after receptor activation are rather contradictory. We investigated the degree of involvement of mitochondrial transcription factors in the biogenesis of mtDNA induced by triiodothyronine. The contribution of TFAM, TFB2M, and helicase Twinkle in thyroid-induced mtDNA biogenesis was assessed. The activation of TFAM and TFB2M expression is shown to be required for the induction of mtDNA biogenesis. The role of helicase Twinkle, the expression induction of which is also observed after triiodothyronine addition, remains unclear. The analysis of factors that activate TFAM and TFB2M expression showed that NRF-1 is the determinative regulator: deficiency of this factor leads to complete collapse of mtDNA biogenesis. However, lack of transcriptional coactivator PGC-1α did not lead to significant reduction in thyroid-induced biogenesis, whereas literature data point to its key role in the biogenesis of mitochondria. Thus, in this study the role of key transcription factors in mtDNA biogenesis induced by triiodothyronine was demonstrated for the first time in a model system.