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

描述（由申请人提供）：氧化应激导致肥胖和2型糖尿病（T2 DM）的线粒体功能障碍，但导致该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，在健康代谢组织中以亚油酸为主。相比之下，肥胖和T2 DM的发生与酰基组成的显著改变相关，从健康的四氢化萘油酰基CL（TLCL）变为富含二十二碳六烯酸（DHA）的CL物质，后者对活性氧（ROS）的氧化损伤高度敏感。氧化的CL起ROS的作用，引发一系列氧化应激和CL氧化的事件，称为“CL过氧化”。“这项资助支持的研究已经确定了ALCAT 1（一种溶血心磷脂酰基转移酶）在与肥胖和T2 DM相关的线粒体功能障碍中的关键作用，它通过催化具有高过氧化指数的CL的合成。该研究还表明，ALCAT 1表达由与肥胖和T2 DM相关的ROS诱导，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，在小鼠中靶向删除ALCAT 1可改善饮食诱导的肥胖症（DIO）及其相关的线粒体功能障碍。引人注目的是，我们的新的初步数据还揭示了ALCAT 1在调节线粒体融合和mtDNA保真度中的意想不到的作用，通过调节线粒体融合所需的线粒体融合蛋白-2（MFN 2），将ALCAT 1的氧化应激与线粒体质量控制缺陷联系起来。基于这些新的初步数据，我们假设ALCAT 1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，这将通过三个特定目标进行测试：目标1将确定ALCAT 1的CL重塑在DIO中的缺陷线粒体质量控制中的作用;目标2将确定ALCAT 1的MFN 2缺陷在DIO中的线粒体功能障碍中的作用;目的3将阐明ALCAT 1调节DIO和T2 DM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，研究途径，整合CL重塑有缺陷的线粒体生物合成和代谢疾病的质量控制。这些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影响，因为病理性CL重塑与所有年龄相关疾病（包括肥胖、T2 DM、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。

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.