Mitochondrial K+ Channels as Anti-Obesity Drug Targets

尽管作出了公共卫生干预努力，但诸如II型糖尿病等代谢性疾病的全球负担仍在继续上升，而这类疾病的一个主要风险因素是肥胖。该项目探索线粒体中可以调节全身能量平衡的新药物靶点，这是肥胖的关键决定因素。在线粒体能量学中，燃料氧化和ATP合成之间的耦合是通过跨膜H+梯度发生的，而线粒体在受热时解偶联以消除这种H+梯度，长期以来一直被视为改变全身能量平衡的潜在药物靶点。然而，直接化学解偶联剂(如二硝基苯酚)受到致命剂量限制毒性的困扰，线粒体解偶联蛋白(UCP)尚未兑现其作为减肥药物靶点的最初承诺。线粒体K+通道是一种被忽视的潜在解偶联途径，其开放与线粒体K+/H+交换器协同可解偶联线粒体。最近我们报道了线粒体中存在Na+激活的K+通道(KNa1.2，Kcnt2基因)，KNA通道激动剂可以在野生型(WT)细胞中解偶联，但不能解偶联Kcnt2-/-细胞。此外，Kcnt2-/-小鼠的体脂升高和血糖调节失调。在高脂肪饮食(HFD)下，他们也会增加更多的体重，表现出更多的肝骨病(与WT相比)。此外，最近关于化合物在高脂饲料喂养的小鼠中显示出治疗益处的报道，忽略了这些化合物是KNA通道开放剂。在线粒体中发现的另一个K+通道是KCa1.1(Kcnma1基因)，值得注意的是，Kcnma1-/-小鼠是肥胖的，而人类Kcnma1基因的多态与肥胖有关。某些活性脂类可以开放KCA通道，包括线粒体中的通道，而可溶性环氧化物水解酶(sEH，降解这些脂类的酶)的抑制剂有助于对抗HFD诱导的病理。这表明线粒体K+通道解偶联是这类药物的作用机制之一。总之，我们假设MITO-K+通道代表了一种新的解偶联途径和潜在的抗肥胖药物靶点。目标1将专注于mito-KNa1.2，旨在开发新的线粒体靶向KNA激动剂，将使用WT和Kcnt2-/-小鼠进行筛选。目的研究MITO-KCa1.1在WT和Kcnma1-/-小鼠体内的药效。我们的目标是开发MITO-K+激动剂作为一类新型的减肥药物。

Despite public health intervention efforts, the global burden of metabolic diseases such as type-II diabetes continues to rise, and a major risk factor for such diseases is obesity. This project explores novel drug targets in mitochondria that can modulate whole-body energy balance, a key determinant of obesity. In mitochondrial energetics, coupling between fuel oxidation and ATP synthesis occurs via a trans-membrane H+ gradient, and the uncoupling of mitochondria to dissipate this H+ gradient as heat has long been viewed as a potential drug target to alter whole-body energy balance. However, direct chemical uncouplers (e.g., dinitrophenol) are plagued by fatal dose-limiting toxicity, and mitochondrial uncoupling proteins (UCPs) have not yet delivered on their initial promise as obesity drug targets. A potential uncoupling pathway that has been largely ignored is mitochondrial K+ channels, whose opening in concert with the mitochondrial K+/H+ exchanger could uncouple mitochondria. Recently we reported a Na+ activated K+ channel (KNa1.2, Kcnt2 gene) exists in mitochondria, and that KNa channel agonists can uncouple in wild-type (WT) but not Kcnt2-/- cells. In addition, Kcnt2-/- mice have elevated body fat and dysregulated blood glucose. They also gain more weight and exhibit more hepatosteatosis (vs. WT) on a high fat diet (HFD). Furthermore, recent reports of compounds exhibiting therapeutic benefits in HFD-fed mice, have overlooked that these compounds are KNa channel openers. Another K+ channel found in mitochondria is KCa1.1 (Kcnma1 gene), and notably Kcnma1-/- mice are obese and human Kcnma1 polymorphisms are linked to obesity. Certain reactive lipids can open KCa channels, including those in mitochondria, and inhibitors of soluble epoxide hydrolase (sEH, the enzyme that degrades these lipids) are beneficial against HFD-induced pathology. This suggests mitochondrial K+ channel uncoupling as a mechanism of action for such drugs. Overall, we hypothesize that mito-K+ channels represent a novel uncoupling pathway and potential anti-obesity drug target. Aim 1 will focus on mito-KNa1.2, aiming to develop novel mitochondria-targeted KNa agonists, to be screened using WT and Kcnt2-/- mice. Aim 2 focuses on mito-KCa1.1, testing drug efficacy in WT and Kcnma1-/- mice. Our goal is to develop mito-K+ agonists as a novel class of anti-obesity drugs.