Thyroid Hormones Regulate the Onset of Osmotic Activity of Rat Liver Mitochondria after Birth *

The effect of thyroid hormone deprivation on the osmotic activity of liver mitochondria from early newborn rats was studied. Experimentally induced hypothyroidism prevented the increase in the osmotic activity of mitochondria observed immediately after birth. Osmotic activity was restored by T4 and T3 treatment to hypothyroid newborns but not when this treatment was supplemented with cycloheximide. Under the same circumstances, streptomycin had no effect. Hypothyroidism abolished the change in the slope of the osmotic curve (plot of inverse absorbance of mitochondrial suspensions incubated in sucrose solutions vs. inverse sucrose concentration) observed in mitochondria from euthyroid newborns at 110–120 mOsm sucrose, suggesting that hypothyroidism prevents the formation of tight physical connections between mitochondrial outer and inner membranes. Thyroid hormone deprivation increased the passive permeability of the mitochondrial inner membrane to protons, resulting in a decreased respiratory control ratio. Hypothyroidism prevented the sharp decrease in the affinity of mitochondria for ATP observed in euthyroid newborns immediately after birth. These results corroborate our previous suggestion (Endocrinology, 1995, 136:4448) that, during the early neonatal period, thyroid hormones control the synthesis of some nucleus-coded protein(s) involved in the assembly of F0,F1-ATPase. (Endocrinology 138: 764–770, 1997) F RAT liver mitochondria have a relatively permeable inner membrane, which correlates with a low respiratory control ratio (RCR) (1). Immediately after birth, however, rat liver mitochondria undergo many significant changes in structure and function. Thus, the inner mitochondrial membrane undergoes a maturation process through which it changes from the relatively permeable membrane observed in the fetus to the fully osmotically active membrane found in the early newborn (1–3). This process correlates with postnatal acquisition of an efficient energy-transducing machinery within the first hour after birth, as shown by the sharp increase in the RCR (1, 4, 5) and in the activities of mitochondrial respiratory complexes (4). Postnatal mitochondrial enrichment in adenine nucleotides (4) has been reported to promote ultrastructural changes that result in a rapid increase in their osmotic activity (1, 6). The effect of adenine nucleotides may be caused by an interaction between ATP and some specific protein of the mitochondrial inner membrane (1–3, 5, 6) Thyroid hormones are known to play an important role in the regulation of the differentiation, development, and growth of most mammalian tissues (7). Mitochondria are considered to be subcellular targets of thyroid hormone action because they affect mitochondrial numbers, morphology (8, 9), molecular structure (10, 11), and function (12). In addition, T4 and T3, also play an important role in the postnatal differentiation and proliferation of liver mitochondria (13). Thus, thyroid hormones regulate the gene expression of the b-catalytic subunit of the mitochondrial F0,F1-ATPase complex (14, 15), considered to be a marker protein of mitochondrial biogenesis during development (4). Along the same line, we recently have shown that thyroid hormones play an important role in postnatal mitochondrial differentiation, as shown by the low RCR and the low activity of the F0,F1-ATPase found in livermitochondria fromhypothyroid