Abstract
Hypothyroidism is a growing medical concern. There are conflicting reports regarding the mechanism of oxidative stress in hypothyroidism. Mitochondrial oxidative stress is pivotal to thyroid dysfunction. The present study aimed to delineate the effects of hepatic inner mitochondrial membrane dysfunction as a consequence of 6-n-propyl-2-thiouracil-induced hypothyroidism in rats. Increased oxidative stress predominance in the submitochondrial particles (SMP) and altered antioxidant defenses in the mitochondrial matrix fraction correlated with hepatocyte apoptosis. In order to check whether the effects caused by hypothyroidism are reversed by T3, the above parameters were evaluated in a subset of T3-treated hypothyroid rats. Complex I activity was inhibited in hypothyroid SMP, whereas T3 supplementation upregulated electron transport chain complexes. Higher mitochondrial H2O2 levels in hypothyroidism due to reduced matrix GPx activity culminated in severe oxidative damage to membrane lipids. SMP and matrix proteins were stabilised in hypothyroidism but exhibited increased carbonylation after T3 administration. Glutathione content was higher in both. Hepatocyte apoptosis was evident in hypothyroid liver sections; T3 administration, on the other hand, exerted antiapoptotic and proproliferative effects. Hence, thyroid hormone level critically regulates functional integrity of hepatic mitochondria; hypothyroidism injures mitochondrial membrane lipids leading to hepatocyte apoptosis, which is substantially recovered upon T3 supplementation.
Highlights
Mitochondria, the powerhouses of eukaryotic cells, are instrumental in regulating the various signaling pathways involved in cell survival and death
Endogenous membrane lipid peroxidation (LPx) expressed in terms of thiobarbituric acid-reactive substances (TBARS) level was significantly enhanced (20.89%, P < 0.01) in submitochondrial particles (SMP) from hypothyroid rats compared to euthyroid (Figure 1(a))
Determination of TBARS level after in vitro incubation with oxidants revealed that hypothyroid SMP were the most susceptible to peroxidation induced by both H2O2 and tertbutyl hydroperoxide which subsided to certain extent after T3 treatment (Figure 1(b))
Summary
Mitochondria, the powerhouses of eukaryotic cells, are instrumental in regulating the various signaling pathways involved in cell survival and death. The electron transport chain, localized in the inner membrane of mitochondrion, is the major source of intracellular reactive oxygen species (ROS), which renders the mitochondrion itself a highly vulnerable target [1, 2]. Thyroid hormones have profound impact upon mitochondrial biogenesis and activity [3, 4]. Hypothyroidism is known to diminish oxygen consumption and promote low metabolism causing disturbances in hemodynamic, cardiac, and renal functions [5]. The electron transport chain complexes and FoF1-ATPase activities are decreased in many tissues in thyroid deficient condition [6]. Hypothyroid status was proposed as useful model to understand the molecular mechanisms involved in ischemia reperfusion, regulation of vascular function, and intravascular metabolism of lipoproteins [5].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
