Mitochondrial K+ Channels as Anti-Obesity Drug Targets

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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.