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3,5,3'-triiodothyronine induces mitochondrial permeability transition mediated by reactive oxygen species and membrane protein thiol oxidation.

Abstract：

:Ca(2+)-loaded rat liver mitochondria treated with 3,5,3'-triiodothyronine (T3) undergo nonspecific inner membrane permeabilization, as evidenced by mitochondrial swelling, a decrease in membrane potential (delta psi), and an increase in the rate of oxygen uptake. T3 analogues thyroxine (T4), 3',5'-diiodothyronine (T2), and 3,5',3'-triiodothyronine (reverse T3), in decreasing order of potency, resulted in a similar but less extensive effect. Permeabilization induced by T3 is dependent on Ca2+ (1 microM) and T3 (0.5-25 microM) concentrations and is inhibited by cyclosporin A, a known inhibitor of mitochondrial permeability transition. Catalase or dithiothreitol also prevents membrane permeabilization, suggesting the participation of membrane protein thiol group oxidation induced by reactive oxygen species. The determination of the mitochondrial membrane protein thiol group content after treatment with Ca2+ and T3 shows a significant decrease, due to thiol oxidation. When mitochondria are incubated in the presence of inorganic phosphate and the protonophore carbonyl cyanide p-trifluoromethoxyphenylhydrazone, mitochondrial swelling still occurs after treatment with T3 and high Ca2+ concentrations, suggesting that mitochondrial permeabilization is not dependent on T3-induced delta psi or matrix pH alterations. Under these experimental conditions, when no oxygen is present in the incubation medium, no permeabilization occurs, suggesting that the permeabilization is dependent on mitochondrial-generated reactive oxygen species. Confirming this hypothesis, superoxide generation in a suspension of submitochondrial particles is increased when T3 is present. Our results lead to the conclusion that T3 induces a situation of oxidative stress in isolated liver mitochondria, with Ca(2+)-mediated membrane protein thiol oxidation and nonspecific inner membrane permeabilization.

journal_name

Arch Biochem Biophys

journal_title

Archives of biochemistry and biophysics

authors

Castilho RF,Kowaltowski AJ,Vercesi AE

doi

10.1006/abbi.1998.0657

subject

Has Abstract

pub_date

1998-06-01 00:00:00

pages

151-7

issue

eissn

0003-9861

issn

1096-0384

pii

S0003-9861(98)90657-9

journal_volume

354

pub_type

杂志文章

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3,5,3'-triiodothyronine induces mitochondrial permeability transition mediated by reactive oxygen species and membrane protein thiol oxidation.