Heart Mitochondrial Function in Acute and in Chronic Hyperthyroidism in Rats

Abstract

The effects of acute versus chronic hyperthyroidism on rat heart mitochondria were explored. Acute, severe hyperthyroidism with an 18% loss of body weight was induced by injecting subcutaneously 10 /i,g/100g/day of triiodothyronine for 6 to 14 days, and chronic, anabolic, moderate hyperthyroidism was induced by placing triiodothyronine in the drinking water at a dose of 25 or 50 yug/100 ml for 15 to 60 days. Mitochondrial function was assessed polarographically using a-ketoglutarate as the oxidizing substrate, and mitochondrial structure was assessed indirectly from changes in rates of swelling in decimolar alkaline salt solutions in vitro. The P-O ratios of heart mitochondria isolated with Nagarse incubation from both types of hyperthyroid rats decreased slightly (15%) but significantly (P = 0.05). Simple dilution of the hyperthyroid mitochondrial suspensions effected a 75% increase in the P-O ratio of the acutely treated rats but only a 19% increase in that of the chronically treated rats. Significantly increased susceptibility to swelling in vitro was exhibited only by the mitochondria of the chronically triiodothyronine-treated rats. On the other hand, only those of the acutely treated rats showed significant increases in the activity of Mg 2 + -stimulated mitochondrial ATPase. These data suggest that the mechanisms whereby excess thyroid hormone in vivo affects the function and structure of isolated rat heart mitochondria vary with the mode of induction and the duration of the hyperthyroid state.ADDITIONAL KEY WORDS thyrotoxicosis triiodothyronine Nagarse incubation oxidative phosphorylation phosphorylative capacity swelling in vitro mitochondrial ATPase and azide mitochondrial free fatty acid • The etiology of cardiac failure observed in the hyperthyroid patient (1, 2) and demonstrated in the chronic hyperthyroid dog (3) is as yet undefined. Studies to date suggest that a biochemical lesion in the area of oxidative phosphorylation is not involved in the heart as in other tissues. Neither sarcosomal function (3-5) nor myocardial levels of the end products of oxidative phosphorylation, phosphorylcreatine and adenosine triphosphate (ATP) (3, 4, 6) were decreased in acute or chronic hyperthyroid animals. Nevertheless, the reduced myocardial resistance to anoxia (7) and the increased oxygen consumption (3,8) in the hyperthyroid heart would appear to reflect involvement of energy production in the mitochondria. The question arises, therefore, as to whether the indices and the species used to assess mitochondrial integrity were sufficiently sensitive to demonstrate thyroidinduced changes in this remarkably resistant organ.This study was designed to explore the effects of a prolonged, chronic anabolic hyperthyroid state on the functional and structural integrity of heart mitochondria of the more susceptible species, the rat, and to compare these effects with those produced by

Mechanisms and Management of Thyroid Disease and Atrial Fibrillation: Impact of Atrial Electrical Remodeling and Cardiac Fibrosis

“…In the mitochondria, various T3 binding sites, such as the adenine nuclear transporter (ANT) have been identified, suggesting a potential effect of thyroid hormones on mitochondrial function [ 57 ]. Hyperthyroid models showed damaged cardiac mitochondrial ultrastructure, increased mitochondrial ATP activity, and oxidative stress [ 59 , 60 , 61 ] ( Figure 1 ). In an ischemia-reperfusion model, T3 supplementation has been shown to improve mitochondrial functions associated with increased myocardial ATP levels and increased aerobic metabolism [ 62 , 63 ].…”