Hypothyroidism affects the expression of the beta-F1-ATPase gene and limits mitochondrial proliferation in rat liver at all stages of development.

Abstract

In order to analyze the role of thyroid hormones in mitochondrial biogenesis, we have studied the expression pattern of the beta subunit of the mitochondrial ATP-synthase complex in liver and in isolated mitochondria during postnatal development of hypothyroid rats. Chemically induced hypothyroidism promoted a significant reduction in body and liver masses at all stages of development. Furthermore, plasma 3,5,3'-triiodo-L-thyronine (T3) and 3,5,3',5'-tetraiodo-L-thyronine (T4) concentrations were significantly reduced in hypothyroid animals when compared to euthyroid animals. Remarkably, steady-state beta-F1-ATPase mRNA levels in livers of hypothyroid animals showed an approximately 50% reduction when compared to age-matched euthyroid rats at all stages of development. The relative amounts of beta-F1-ATPase protein determined in isolated mitochondria of 1-day-old and adult hypothyroid animals were similar to those determined in mitochondria of age-matched euthyroids, indicating that hypothyroidism does not affect organelle differentiation in the liver of suckling and adult rats. In contrast, the relative amount of beta-F1-ATPase protein in liver homogenates varied (0-30% reduction) due to the hypothyroid condition during development. These findings suggest the existence of compensatory mechanisms operating at the translational and/or post-translational levels which promote proliferation of mitochondria in the hypothyroid liver. However, when the liver mass was considered, hypothyroidism significantly reduced overall mitochondrial proliferation in rat liver. Interestingly, the effects of thyroid hormones on the biogenesis of the ATP synthase complex at latter stages of development provide an example in which the hypothyroid condition limits the expression of the nuclear-encoded gene with no apparent effect on the expression of the mitochondrial-encoded genes (ATP synthase subunits 6-8).