Kundumani-Sridharan Venkatesh, Raghavan Somasundaram, Kumar Sudhir, Das Kumuda C
Department of Internal Medicine, Texas Tech University Health Sciences Center, 3601 4th Street, Lubbock, TX 79430, USA.
Department of Internal Medicine, Texas Tech University Health Sciences Center, 3601 4th Street, Lubbock, TX 79430, USA.
Redox Biol. 2025 Jul;84:103678. doi: 10.1016/j.redox.2025.103678. Epub 2025 May 13.
Cytosolic thioredoxin (Trx) is a critical redox protein that converts protein disulfides to thiols via catalytic activity of thioredoxin reductase-1 (TrxR1) and NADPH. Thioredoxin-2 (Trx2) is a mitochondria-localized isoform. It is generally believed that Trx and Trx2 perform similar functions within the cytosol and mitochondria respectively. Here, we demonstrate that cytosolic Trx shuttles into mitochondria in the presence of normal levels of Trx2 in physiological state and higher levels of Trx translocate to mitochondria in oxidative stress conditions such as exposure to high concentrations of oxygen. This shuttle is required to maintain mitochondrial structure and function during physiological and oxidative stress conditions. Further, reduced Trx (Trx-SH) shuttle into mitochondria to protect against the downregulation of several mitochondrially coded genes and proteins of respiratory chain complexes in oxidative stress. Translocation of Trx occurs only in the reduced state as oxidized or cysteine mutant Trx is unable to translocate to the mitochondria. Accumulation of mitochondrial DNA damage product 8-Oxo-dG in hyperoxia is decreased in the presence of higher levels of cytosolic Trx within the mitochondrion. Collectively, our data demonstrate that shuttling of reduced cytosolic Trx into mitochondria protects against mitochondrial DNA damage, decreased gene and protein expression of respiratory chain complexes and mitochondrial dysfunction resulting in restoration of their native function and cell survival in physiological and oxidative stress conditions.
胞质硫氧还蛋白（Trx）是一种关键的氧化还原蛋白，它通过硫氧还蛋白还原酶-1（TrxR1）和NADPH的催化活性将蛋白质二硫键转化为硫醇。硫氧还蛋白-2（Trx2）是一种定位于线粒体的异构体。一般认为Trx和Trx2分别在胞质溶胶和线粒体内发挥相似的功能。在此，我们证明在生理状态下，当存在正常水平的Trx2时，胞质Trx会穿梭进入线粒体，而在氧化应激条件下，如暴露于高浓度氧气时，较高水平的Trx会转位到线粒体。这种穿梭在生理和氧化应激条件下对于维持线粒体结构和功能是必需的。此外，还原型Trx（Trx-SH）穿梭进入线粒体以防止氧化应激时几个线粒体编码基因和呼吸链复合物蛋白的下调。Trx的转位仅在还原状态下发生，因为氧化型或半胱氨酸突变型Trx无法转位到线粒体。在高氧环境中，当线粒体内存在较高水平的胞质Trx时，线粒体DNA损伤产物8-氧代-dG的积累会减少。总体而言，我们的数据表明，还原型胞质Trx穿梭进入线粒体可防止线粒体DNA损伤、呼吸链复合物基因和蛋白表达的降低以及线粒体功能障碍，从而在生理和氧化应激条件下恢复其天然功能并促进细胞存活。
