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（T2DM）的线粒体功能障碍，但其分子机制尚不清楚。心磷脂（Cardiolipin， CL）是线粒体氧化磷酸化和线粒体生物发生所必需的线粒体膜磷脂。CL的生物学功能是由其酰基组成决定的，在健康的代谢组织中以亚油酸为主。相比之下，肥胖和T2DM的发病与酰基组成的显著改变有关，从健康的四脂油基CL （TLCL）到富含二十二碳六烯酸（DHA）的CL物种，后者对活性氧（ROS）的氧化损伤高度敏感。氧化后的CL发挥ROS的作用，引发一系列氧化应激和CL氧化事件，称为“CL过氧化”。该基金支持的研究发现，溶心磷脂酰基转移酶ALCAT1通过催化高过氧化指数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，肥胖和T2DM相关的ROS诱导ALCAT1表达，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ALCAT1可以改善饮食性肥胖（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GTPase -2（线粒体融合所需的GTPase -2）在调节线粒体融合和mtDNA保真度方面的意想不到的作用，将ALCAT1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ALCAT1的CL重塑通过损害线粒体融合而导致DIO的线粒体功能障碍，我们将通过三个具体目标进行验证：Aim 1将确定ALCAT1的CL重塑在DIO线粒体质量控制缺陷中的作用；目的2将确定ALCAT1引起的MFN2缺乏在DIO线粒体功能障碍中的作用；Aim 3将阐明ALCAT1调节DIO和T2DM线粒体自噬的分子机制。本研究的成功完成将为研究代谢性疾病中CL重塑与线粒体缺陷生物发生和质量控制的整合途径开辟新的方向。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具有深远的意义，因为病理性CL重塑涉及与所有年龄相关疾病相关的线粒体功能障碍，包括肥胖、2型糖尿病、心血管疾病、癌症和神经变性。

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.