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Modulation Of Liver Mitochondrial NOS Is Implicated In Thyroid-dependent Regulation Of O2 Uptake

María Cecilia Carreras, Jorge G. Peralta, Daniela P. Converso, Paola V. Finocchietto, Inés Rebagliati, Angel A. Zaninovich, Juan José Poderoso

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Changes in O2 uptake at different thyroid status have been explained on the basis of the modulation of mitochondrial enzymes and membrane biophysical properties. Regarding the nitric oxide (NO) effects, we tested whether liver mitochondrial nitric oxide synthase (mtNOS) participates in the modulation of O2 uptake in thyroid disorders. Wistar rats were inoculated with 400 μCi131I (hypothyroid group), 20 μg thyroxine (T4)/100 g body wt administered daily for 2 wk (hyperthyroid group) or vehicle (control). Basal metabolic rate, mitochondrial function, and mtNOS activity were analyzed. Systemic and liver mitochondrial O2 uptake and cytochrome oxidase activity were lower in hypothyroid rats with respect to controls; mitochondrial parameters were further decreased byl-arginine (−42 and −34%, P < 0.05), consistent with 5- to 10-fold increases in matrix NO concentration. Accordingly, mtNOS expression (75%) and activity (260%) were selectively increased in hypothyroidism and reverted by hormone replacement without changes in other nitric oxide isoforms. Moreover, mtNOS activity correlated with serum 3,5,3′-triiodothyronine (T3) and O2 uptake. Increased mtNOS activity was also observed in skeletal muscle mitochondria from hypothyroid rats. Therefore, we suggest that modulation of mtNOS is a substantial part of thyroid effects on mitochondrial O2 uptake.