Original Contribution EFFECT OF THYROID STATE ON SUSCEPTIBILITY TO OXIDANTS AND SWELLING OF MITOCHONDRIA FROM RAT TISSUES PAOLA VENDITTI,RAFFAELLA DE ROSA, and SERGIO DI MEO Dipartimento di Fisiologia Generale ed Ambientale, Universit` a di Napoli, Napoli, Italy (Received 5 February 2003; Revised 19 May 2003; Accepted 23 May 2003) Abstract—The effects of the thyroid state on oxidative damage, antioxidant capacity, susceptibility to in vitro oxidative stress and Ca 2+ -induced permeabilization of mitochondria from rat tissues (liver, heart, and gastrocnemious muscle) were examined. Hypothyroidism was induced by administering methimazole in drinking water for 15 d. Hyperthyroid- ism was elicited by a 10 d treatment of hypothyroid rats with triiodothyronine (10 g/100 g body weight). Mitochondrial levels of hydroperoxides and protein-bound carbonyls significantly decreased in hypothyroid tissues and were reported above euthroid values in hypothyroid rats after T 3 treatment. Mitochondrial vitamin E levels were not affected by changes of animal thyroid state. Mitochondrial Coenzyme Q9 levels decreased in liver and heart from hypothyroid rats and increased in all hyperthyroid tissues, while Coenzyme Q10 levels decreased in hypothyroid liver and increased in all hyperthyroid tissues. The antioxidant capacity of mitochondria was not significantly different in hypothyroid and euthyroid tissues, whereas it decreased in the hyperthyroid ones. Susceptibility to in vitro oxidative challenge decreased in mitochondria from hypothyroid tissues and increased in mitochondria from hyperthyroid tissues, while susceptibility to Ca 2+ -induced swelling decreased only in hypothyroid liver mitochondria and increased in mitochondria from all hyperthyroid tissues. The tissue-dependence of the mitochondrial susceptibility to stressful conditions in altered thyroid states can be explained by different thyroid hormone-induced changes in mitochondrial ROS production and relative amounts of mitochondrial hemoproteins and antioxidants. We suggest that susceptibilities to oxidants and Ca 2+ -induced swelling may have important implications for the thyroid hormone regulation of the turnover of proteins and whole mitochondria, respectively. © 2003 Elsevier Inc. Keywords—Free radicals, Mitochondria, Thyroid hormone, Lipid peroxidation, Oxidative stress, Antioxidants INTRODUCTION It has long been known that in vertebrates hyperthyroid- ism leads to an acceleration of the basal metabolic rate [1], which is associated with increased cellular respira- tion in target tissues such as liver, kidney, heart, and skeletal muscle [1,2]. More recently, it has been sug- gested that the hypermetabolic state in hyperthyroidism results in oxidative tissue injury, secondary to increased production of reactive oxygen species (ROS) [3]. The ability of thyroid hormone to induce oxidative stress in some tissues is demonstrated by increases in liver [4,5], heart, and muscle [5,6] lipid peroxidation and liver pro- tein oxidation [7] in hyperthyroid rats. However, the mechanisms underlying this have not been well estab- lished. Oxidative stress-linked oxidation of biomolecules might be triggered by high rates of ROS generation and depressed antioxidant defenses. Previous studies inves- tigating changes in the tissue levels of scavengers and activities of antioxidant enzymes have been controversial [6,8 –11]. Using an enhanced luminescence technique, we found that the responses to thyroid state changes are tissue-specific. In fact, in comparison to euthyroid con- trols, liver and heart, but not muscle, from both hypo- thyroid and hyperthyroid rats exhibited lower overall antioxidant capacity [5]. Furthermore, liver, heart, and muscle from hyperthyroid rats and heart and muscle, but not liver, from hypothyroid animals exhibited higher susceptibility to in vitro oxidative challenge. Scant information is available on the effects of altered thyroid states on antioxidant capacity, resistance to stress, and oxidative damage of mitochondria. Such in- Address correspondence to: Dr. Sergio Di Meo, Dipartimento di Fisiologia Generale ed Ambientale, Universita ` di Napoli “Federico II”, Via Mezzocannone 8, I-80134, Napoli, Italy; Tel: +039 (081) 253- 5076; Fax: +039 (081) 253-5090; E-Mail: dimeo@biol.dgbm.unina.it. Free Radical Biology & Medicine, Vol. 35, No. 5, pp. 485– 494, 2003 Copyright © 2003 Elsevier Inc. Printed in the USA. All rights reserved 0891-5849/03/$–see front matter doi:10.1016/S0891-5849(03)00331-9 485