Barshop Institute for Longevity and Aging Studies, University of Texas Health San Antonio, San Antonio, TX, USA.
Department of Radiation Oncology, Long School of Medicine, University of Texas Health San Antonio, San Antonio, TX, USA.
Commun Biol. 2022 May 16;5(1):467. doi: 10.1038/s42003-022-03405-w.
Mitochondrial dysfunction is a key driver of diabetes and other metabolic diseases. Mitochondrial redox state is highly impactful to metabolic function but the mechanism driving this is unclear. We generated a transgenic mouse which overexpressed the redox enzyme Thioredoxin Reductase 2 (TrxR2), the rate limiting enzyme in the mitochondrial thioredoxin system. We found augmentation of TrxR2 to enhance metabolism in mice under a normal diet and to increase resistance to high-fat diet induced metabolic dysfunction by both increasing glucose tolerance and decreasing fat deposition. We show this to be caused by increased mitochondrial function which is driven at least in part by enhancements to the tricarboxylic acid cycle and electron transport chain function. Our findings demonstrate a role for TrxR2 and mitochondrial thioredoxin as metabolic regulators and show a critical role for redox enzymes in controlling functionality of key mitochondrial metabolic systems.
线粒体功能障碍是糖尿病和其他代谢性疾病的关键驱动因素。线粒体氧化还原状态对代谢功能有很大的影响，但驱动这种状态的机制尚不清楚。我们生成了一种过表达氧化还原酶硫氧还蛋白还原酶 2（TrxR2）的转基因小鼠，TrxR2 是线粒体硫氧还蛋白系统中的限速酶。我们发现，增加 TrxR2 的表达可以增强正常饮食下小鼠的代谢，并通过提高葡萄糖耐量和减少脂肪沉积来增加对高脂肪饮食诱导的代谢功能障碍的抵抗力。我们表明，这是由于线粒体功能增强所致，至少部分是由于三羧酸循环和电子传递链功能的增强。我们的研究结果表明 TrxR2 和线粒体硫氧还蛋白作为代谢调节剂的作用，并表明氧化还原酶在控制关键线粒体代谢系统的功能方面起着关键作用。
