Isocitrate dehydrogenase 2 (IDH2) is an NADP+-dependent enzyme that catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate in the mitochondrial matrix, and is critical for the production of NADPH to limit the accumulation of mitochondrial reactive oxygen species (ROS). Here, we showed that high-fat diet (HFD) feeding resulted in accelerated weight gain in the IDH2KO mice due to a reduction in whole-body energy expenditure. Moreover, the levels of NADP+, NADPH, NAD+, and NADH were significantly decreased in the brown adipose tissue (BAT) of the HFD-fed IDH2KO animals, accompanied by decreased mitochondrial function and reduced expression of key genes involved in mitochondrial biogenesis, energy expenditure, and ROS resolution. Interestingly, these changes were partially reversed when the antioxidant butylated hydroxyanisole was added to the HFD. These observations reveal a crucial role for IDH2 in limiting ROS-dependent mitochondrial damage when BAT metabolism is normally enhanced to limit weight gain in response to dietary caloric overload.

中文翻译：

---

异柠檬酸脱氢酶2通过限制棕色脂肪组织对线粒体的氧化损伤，保护小鼠免受高脂饮食诱导的代谢压力。

异柠檬酸脱氢酶2（IDH2）是一种依赖NADP +的酶，可催化线粒体基质中异柠檬酸氧化脱羧为α-酮戊二酸，对于限制线粒体活性氧（ROS）的积累对NADPH的生产至关重要。在这里，我们显示高脂饮食（HFD）喂养由于减少了全身能量消耗而导致IDH2KO小鼠体重增加加速。此外，喂食HFD的IDH2KO动物的棕色脂肪组织（BAT）中NADP +，NADPH，NAD +和NADH的水平显着降低，伴随着线粒体功能的降低以及与线粒体生物发生，能量消耗有关的关键基因的表达降低和ROS分辨率。有趣的是 当将抗氧化剂丁基化羟基茴香醚添加到HFD中时，这些变化会部分逆转。这些观察结果表明，当BAT代谢通常被增强以限制体重增加以应对饮食热量超负荷时，IDH2在限制ROS依赖性线粒体损伤中起着至关重要的作用。