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

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）：氧化应激导致肥胖和 2 型糖尿病 (T2DM) 中的线粒体功能障碍，但其原因的分子机制仍不清楚。心磷脂 (CL) 是氧化磷酸化和线粒体生物合成所需的线粒体膜磷脂。 CL的生物学功能由其酰基组成决定，在健康的代谢组织中，酰基组成以亚油酸为主。相比之下，肥胖和 T2DM 的发生与酰基组成的显着改变相关，从健康的四亚油酰 CL (TLCL) 到富含二十二碳六烯酸 (DHA) 的 CL 种类，DHA 对活性氧 (ROS) 的氧化损伤高度敏感。 ）。氧化的 CL 以 ROS 的形式发挥作用，引发一系列氧化应激和 CL 氧化事件，称为“CL 过氧化”。该资助支持的研究已确定 ALCAT1（一种溶心磷脂酰基转移酶）通过催化具有高过氧化指数的 CL 的合成，在与肥胖和 T2DM 相关的线粒体功能障碍中发挥关键作用。研究还表明，ALCAT1 表达是由与肥胖和 T2DM 相关的 ROS 诱导的，引发氧化应激、线粒体功能障碍和胰岛素抵抗的恶性循环。因此，我们表明，在小鼠中定向删除 ALCAT1 可改善饮食诱导的肥胖 (DIO) 及其相关的线粒体功能障碍。引人注目的是，我们的新初步数据还揭示了 ALCAT1 通过调节线粒体融合所需的 GTP 酶 mitofusin-2 (MFN2) 在调节线粒体融合和 mtDNA 保真度方面发挥着意想不到的作用，将 ALCAT1 的氧化应激与有缺陷的线粒体质量控制联系起来。基于这些新的初步数据，我们假设 ALCAT1 的 CL 重塑通过损害线粒体融合而导致 DIO 中的线粒体功能障碍，这将通过三个具体目标进行测试：目标 1 将确定 ALCAT1 的 CL 重塑在有缺陷的线粒体质量控制中的作用。迪奥；目标 2 将确定 ALCAT1 导致的 MFN2 缺乏在 DIO 线粒体功能障碍中的作用；目标3将阐明ALCAT1在DIO和T2DM中调节线粒体自噬的分子机制。拟议研究的成功完成将为将 CL 重塑与代谢疾病中缺陷的线粒体生物发生和质量控制相结合的研究途径开辟新的方向。这一信息将对设计针对肥胖和其他年龄相关疾病的新治疗策略产生深远的影响，因为病理性 CL 重塑与所有年龄相关疾病（包括肥胖、T2DM、心血管疾病、癌症和神经退行性疾病）相关的线粒体功能障碍有关。 。