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，包括防止心脏缺血/再灌注损伤， 细胞，癌细胞的抗增殖，动脉粥样硬化和血管衰老的衰减 在高脂肪饮食、小鼠寿命延长和超重和肥胖小鼠体重减轻的背景下， 肥胖患者。尽管已经使用了超过半个世纪，但是， 二甲双胍尚未确立。使用营养敏感的细胞为基础的战略，Gohil等。 （Nature Biotechnology 28：249，2010）最近筛选了约3700种可商购获得的化学品， 化合物，并确定了80多个干扰能源生产的 线粒体，类似于二甲双胍。几种最有效的化合物是已知的 直接抑制线粒体，但以前大多数与能量代谢无关。 在那些剩余的化合物中，几乎所有的化合物在生理pH下都带正电荷， 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， 扩散到带负电荷的线粒体基质，只要该分子是天然的， 膜渗透或可以通过转运蛋白进入。根据基本原则， 电化学梯度（即，能斯脱平衡），积累一个稳定的积极 线粒体基质中的带电化合物将降低净质子动力 可用于驱动ATP合成，从而降低有氧能量的效率 生产该项目的中心假设是，有机阳离子减少线粒体 生物能源效率，以及随之而来的能源消耗的增加是 这类化合物改善血糖控制的潜在机制 高脂肪饮食引起的胰岛素抵抗。目标1将确定有机阳离子对 线粒体和细胞生物能量功能。目标2将决定生化 有机阳离子改变生物能功能的机制和缓解特性， 目标3将确定线粒体效率降低是否是潜在的机制， 所述有机阳离子防止高脂肪饮食引起的肥胖和胰岛素抗性。这 一个项目预计将大大推进我们对线粒体生物能量如何的理解， 可以操纵该功能以预防或治疗糖尿病以及其他相关疾病。 代谢紊乱

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.