Regulation of Mitochondrial Dysfunction in Diet-Induced Obesity by ALCAT-1

ALCAT-1 对饮食引起的肥胖中线粒体功能障碍的调节

• 批准号: 8996564
• 负责人: YUGUANG SHI
• 金额: $ 33.17万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-14 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8996564
• 关键词: Autophagocytosis; Biogenesis; Biological Process; Cardiolipins; Cardiovascular Diseases; Cells; DNA copy number; Data; Defect; Diabetes Mellitus; Diet; Disease; Docosahexaenoic Acids; Doxycycline; Enzymes; Etiology; Event; Genes; Grant; Guanosine Triphosphate Phosphohydrolases; Health; Insulin Resistance; Link; Linoleic Acids; Lipids; Malignant Neoplasms; Metabolic; Metabolic Diseases; Mitochondria; Mitochondrial DNA; Molecular; Mus; Nerve Degeneration; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oxidative Phosphorylation; Oxidative Stress; Pathway interactions; Phospholipids; Play; Process; Quality Control; Reactive Oxygen Species; Regulation; Research; Research Support; Role; Skeletal Muscle; Source; Testing; Tissues; Transacylase; Work; age related; base; db/db mouse; design; indexing; insulin sensitivity; knock-down; loss of function; mitochondrial autophagy; mitochondrial dysfunction; mitochondrial membrane; novel; novel therapeutic intervention; overexpression; oxidation; oxidative damage; peroxidation; prevent; Autophagocytosis; Biogenesis; Biological Process; Cardiolipins; Cardiovascular Diseases; Cells; DNA copy number; Data; Defect; Diabetes Mellitus; Diet; Disease; Docosahexaenoic Acids; Doxycycline; Enzymes; Etiology; Event; Genes; Grant; Guanosine Triphosphate Phosphohydrolases; Health; Insulin Resistance; Link; Linoleic Acids; Lipids; Malignant Neoplasms; Metabolic; Metabolic Diseases; Mitochondria; Mitochondrial DNA; Molecular; Mus; Nerve Degeneration; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oxidative Phosphorylation; Oxidative Stress; Pathway interactions; Phospholipids; Play; Process; Quality Control; Reactive Oxygen Species; Regulation; Research; Research Support; Role; Skeletal Muscle; Source; Testing; Tissues; Transacylase; Work; age related; base; db/db mouse; design; indexing; insulin sensitivity; knock-down; loss of function; mitochondrial autophagy; mitochondrial dysfunction; mitochondrial membrane; novel; novel therapeutic intervention; overexpression; oxidation; oxidative damage; peroxidation; prevent

DESCRIPTION (provided by applicant): Oxidative stress causes mitochondrial dysfunction in obesity and type 2 diabetes mellitus (T2DM), but the molecular mechanisms underlying the cause remain poorly elucidated. Cardiolipin (CL) is a mitochondrial membrane phospholipid required for oxidative phosphorylation and mitochondrial biogenesis. The biological function of CL is determined by its acyl composition, which is dominated by linoleic acid in healthy metabolic tissues. In contrast, the onset of obesity and T2DM is associated with a significant alteration of acyl composition from the healthy tetralinoleoyl CL (TLCL) to the CL species enriched with docosahexaenoic acid (DHA) which is highly sensitive to oxidative damage by reactive oxygen species (ROS). Oxidized CL functions as ROS, initiating a chain of events of oxidative stress and CL oxidation known as "CL peroxidation." Research supported by this grant has identified a key role of ALCAT1, a lysocardiolipin acyltransferse, in mitochondrial dysfunction associated with obesity and T2DM by catalyzing the synthesis of CL with a high peroxidation index. The research has also shown that ALCAT1 expression is induced by ROS associated with obesity and T2DM, triggering a vicious cycle of oxidative stress, mitochondrial dysfunction, and insulin resistance. Consequently, we show that targeted deletion of ALCAT1 in mice ameliorates diet-induced obesity (DIO) and its related mitochondrial dysfunctions. Strikingly, our new preliminary data also reveal an unexpected role of ALCAT1 in regulating mitochondrial fusion and mtDNA fidelity through the modulation of mitofusin-2 (MFN2), a GTPase required for mitochondrial fusion, linking oxidative stress by ALCAT1 to defective mitochondrial quality control. Based on these new preliminary data, we hypothesize that CL remodeling by ALCAT1 causes mitochondrial dysfunction in DIO by impairing mitochondrial fusion, which will be tested by three specific aims: Aim 1 will identify the role of CL remodeling by ALCAT1 in defective mitochondrial quality control in DIO; Aim 2 will determine the role of MFN2 deficiency by ALCAT1 in mitochondrial dysfunction in DIO; and Aim 3 will elucidate the molecular mechanism by which ALCAT1 regulates mitochondrial autophagy in DIO and T2DM. Successful completion of the proposed studies will open a new direction to study pathways that integrate CL remodeling to defective mitochondrial biogenesis and quality control in metabolic diseases. This information will have profound implications in designing new therapeutic strategies against obesity and other age-related diseases, because pathological CL remodeling is implicated in mitochondrial dysfunction associated with all the age-related diseases, including obesity, T2DM, cardiovascular diseases, cancer, and neurodegeneration.

描述（由申请人提供）：氧化应激会导致肥胖症和2型糖尿病（T2DM）中的线粒体功能障碍，但是该原因所产生的分子机制仍然很差。 Cardiolipin（CL）是一种线粒体膜磷脂，需要用于氧化磷酸化和线粒体生物发生。 CL的生物学功能由其酰基组成决定，该酰基成分由健康代谢组织中的亚油酸主导。相比之下，肥胖和T2DM的发作与健康的四苯甲酰基CL（TLCL）的酰基组成显着改变有关，到富含二十六六烯酸（DHA）的Cl物种，这对反应性氧化物种对氧化损伤高度敏感。氧化的Cl充当ROS，启动了一系列氧化应激和CL氧化事件，称为“ CL过氧化”。该赠款支持的研究已经确定了Alcat1（一种溶血性脂蛋白酰基转移剂）在与肥胖和T2DM相关的线粒体功能障碍中，通过用高过氧化指数催化CL的合成。该研究还表明，与肥胖和T2DM相关的ROS诱导了Alcat1的表达，从而触发了氧化应激，线粒体功能障碍和胰岛素抵抗的恶性循环。因此，我们表明，在小鼠中靶向缺失alcat1可以改善饮食诱导的肥胖症（DIO）及其相关的线粒体功能障碍。令人惊讶的是，我们的新初步数据还揭示了Alcat1通过调节线粒体蛋白-2（MFN2）来调节线粒体融合和mtDNA fidelity的意外作用，这是线粒体融合所需的GTPase（MFN2），这是通过Alcat1链接到有缺陷的线粒体氧化应激，与有缺陷的线粒体质量控制。基于这些新的初步数据，我们假设ALCAT1通过损害线粒体融合而在DIO中进行CL重塑会导致线粒体功能障碍，这将通过三个特定的目的进行测试，这将通过三个特定的目标进行测试：AIM 1将确定Alcat1在DiO中alcat1在DIO中的CL重塑作用。 AIM 2将确定Alcat1在DIO中线粒体功能障碍中MFN2缺乏症的作用； AIM 3将阐明ALCAT1调节DIO和T2DM中线粒体自噬的分子机制。成功完成拟议的研究将开辟一个新的方向，以研究将CL重塑与代谢疾病中有缺陷的线粒体生物发生和质量控制的途径相结合。该信息将对针对肥胖症和其他与年龄相关的疾病的新治疗策略产生深远的影响，因为病理CL重塑与与所有与年龄相关的疾病有关的线粒体功能障碍与包括肥胖，T2DM，T2DM，心血管疾病，癌症，癌症和神经脱发有关的线粒体功能障碍。