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

有机阳离子对线粒体能量驱动力和代谢效率的影响

基本信息

批准号：
9306069
负责人：
P Darrell Neufer
金额：
$ 38.76万
依托单位：
EAST CAROLINA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9306069
关键词：
ATP Synthesis Pathway Aerobic Affect Atherosclerosis Berberine Biguanides Biochemical Bioenergetics Biological Markers Biotechnology Blood Vessels Body Weight decreased Cardiac Cations Cell Culture Techniques Cells Charge Chemicals Chronic Clinical Complex Cultured Cells Diabetes Mellitus Diffuse Disease Dose Drug usage Electron Transport Energy Metabolism Epidemiology FDA approved Fatty acid glycerol esters Free Energy Gluconeogenesis High Fat Diet Hydrogen Peroxide Insulin Resistance Kinetics Link Liver Longevity Malignant Neoplasms Mediating Membrane Membrane Potentials Metabolic Metabolic Diseases Metabolism Metformin Mitochondria Mitochondrial Matrix Molecular Mus Nature Non-Insulin-Dependent Diabetes Mellitus Nutrient Obesity Overweight Oxidative Phosphorylation Oxygen Consumption Paper Patients Pharmaceutical Preparations Pharmacotherapy Phosphotransferases Physiological Plasma Production Property Proton-Motive Force Reperfusion Injury Respiration Signal Transduction Skeletal Muscle Stress System Testing Weight-Loss Drugs attenuation base cancer cell driving force glycemic control improved in vivo inhibitor/antagonist insulin sensitivity loss of function middle age mitochondrial membrane novel prevent senescence

项目摘要

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.

有机阳离子和线粒体效率抽象的二甲双胍是治疗 2 型糖尿病最广泛使用的药物，也被认为具有多种功效其他有益作用，包括防止心脏缺血/再灌注损伤细胞、抗癌细胞增殖、减轻动脉粥样硬化和血管衰老在高脂肪饮食的背景下，小鼠寿命延长，超重和超重者体重减轻肥胖患者。尽管使用了半个多世纪，但其主要作用机制二甲双胍尚未确定。 Gohil 等人使用营养敏感的基于细胞的策略。 (Nature Biotechnology 28:249, 2010) 最近筛选了约 3700 种市售化学品并鉴定出 80 多种干扰能源生产的化合物线粒体，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，但大多数之前并未与能量代谢相关。在那些剩余的化合物中，几乎所有化合物在生理 pH 值下都带有正电荷，也与二甲双胍类似。任何带正电的小分子化合物都会进入细胞并扩散到带负电的线粒体基质，前提是该分子是天然的膜渗透或可以通过转运蛋白进入。基于以下基本原则电化学梯度（即能斯特平衡），稳定的正电荷的积累线粒体基质中的带电化合物会降低净质子动力可驱动 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效率，随之而来的能量消耗的增加是此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功能。目标 2 将确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机制：哪些有机阳离子可以防止高脂肪饮食引起的肥胖和胰岛素抵抗。这该项目预计将显着增进我们对线粒体生物能量如何发挥作用的理解可以操纵功能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。