Impact of organic cations on mitochondrial energetic driving forces and metabolic efficiency

有机阳离子与线粒体效率 摘要 二甲双胍是治疗2型糖尿病最广泛的处方药，也被认为是一种 其他有益作用包括对心脏缺血/再灌注损伤的保护作用 细胞，癌细胞的抗增殖，动脉粥样硬化和血管衰老的减弱 在高脂肪饮食的背景下，延长小鼠的寿命，以及超重和 肥胖的病人。尽管已经使用了半个多世纪，但它的主要作用机制 二甲双胍尚未被建立。使用基于营养敏感细胞的策略，Gohil等人。 (自然生物技术28：249,2010)最近筛选出约3700种可商业化的化学品 并确定了80多种干扰能量产生的化合物 线粒体，类似于二甲双胍。几种最有效的化合物已为人所知 直接抑制线粒体，但大多数以前没有与能量代谢有关。 在这些剩余的化合物中，几乎所有的化合物在生理pH值下都带有正电荷 类似于二甲双胍。任何带正电荷的小分子化合物都会进入细胞并 扩散到带负电荷的线粒体基质，前提是分子是天然的 膜意味着或可以通过传送器进入。基于以下基本原则 电化学梯度(即能斯特平衡)，稳定的正积累 线粒体基质中的带电化合物会降低质子净动力 可用于驱动ATP合成，从而降低有氧能量的效率 制作。这个项目的中心假设是有机阳离子减少了线粒体 生物能效率，以及随之而来的能源支出的增加 这类化合物改善血糖控制的潜在机制 高脂饮食导致胰岛素抵抗。目标1将确定有机阳离子对 线粒体和细胞的生物能量功能。目标2将决定生化 有机阳离子改变生物能量功能的机理(S)及其缓解特性， 目标3将确定线粒体效率降低是否是潜在的机制，通过 哪些有机阳离子可以预防高脂饮食引起的肥胖和胰岛素抵抗。这 该项目有望显著提高我们对线粒体生物能量学的理解 功能可以被操控来预防或治疗糖尿病以及其他相关疾病 患有新陈代谢障碍。

Organic Cations and Mitochondrial Efficiency Abstract Metformin, the most widely prescribed drug for type 2 diabetes, is also recognized for a variety of other beneficial effects including protection against ischemia/reperfusion injury in cardiac cells, anti-proliferation in cancer cells, attenuation of atherosclerosis and vascular senescence in the context of high fat diets, extension of lifespan in mice, and weight loss in overweight and obese patients. Despite over half a century of use, the primary mechanism of action of metformin has not been established. Using a nutrient sensitive cell-based strategy, Gohil et al. (Nature Biotechnology 28:249, 2010) recently screened ~3700 commercially available chemical compounds and identified more than 80 that interfere with energy production by the mitochondria, similar to metformin. Several of the most potent compounds were already known to directly inhibit mitochondria, but most had not been previously linked to energy metabolism. Of those remaining compounds, nearly all carry a positive charge at physiological pH, also similar to metformin. Any positively charged small molecular compound will enter cells and diffuse to the negatively charged mitochondrial matrix, provided the molecule is naturally membrane permeant or can enter via a transporter. Based on basic principles of electrochemical gradients (i.e., Nernst equilibria), the accumulation of a stable positively charged compound in the mitochondrial matrix will decrease the net proton motive force available to drive ATP synthesis, thereby decreasing the efficiency of aerobic energy production. The central hypothesis of this project is that organic cations decrease mitochondrial bioenergetic efficiency, and that the consequent increase in energy expenditure is the underlying mechanism by which such compounds improve glycemic control in the context of high fat diet-induced insulin resistance. Aim 1 will establish the impact of organic cations on mitochondrial and cellular bioenergetic function. Aim 2 will determine the biochemical mechanism(s) and mitigating properties by which organic cations alter bioenergetic function, and Aim 3 will determine if decreased mitochondrial efficiency is the underlying mechanism by which organic cations protect against high fat diet-induced obesity and insulin resistance. This project is expected to significantly advance our understanding of how mitochondrial bioenergetic function may be manipulated to prevent or treat diabetes, as well as other diseases associated with disorders of metabolism.