心磷脂重塑酶 ALCAT1调控线粒体功能紊乱与代谢疾病的机制研究

The onset of obesity and type 2 diabetes mellitus (T2DM) causes mitochondrial dysfunction, which is implicated in the pathogenesis of these diseases through poorly defined mechanisms. Cardiolipin (CL) is a mitochondria specific phospholipid which regulates every aspect of mitochondrial function, including mitochondrial membrane structure, oxidative phosphorylation, ATP production, fusion/fission, mitophagy, biogenesis, inflammation, and apoptosis. The onset of obesity and T2DM causes depletion of tetralinoleoyl cardiolipin (TLCL), the signature structure of CL in metabolic tissues, and enrichment of docosahexaenoic acid . This change renders CL highly sensitive to oxidative damage by reactive oxygen species (ROS). Oxidized CL not only causes mitochondrial dysfunction, but also becomes a major source of ROS as lipid peroxides, further exacerbating oxidative damage of mitochondria.” However, the metabolic pathways that regulates this defective CL remodeling process remains elusive. We have recently identified a novel pathway by which ROS regulate mitochondrial dysfunction. This pathways is mediated by ALCAT1, the first and only lysocardiolipin acyltransferse initially cloned by us. Our previous and ongoing work show that ALCAT1 catalyzes CL remodeling with DHA and other long polyunsaturated fatty acids, leading to mitochondrial dysfunction in obesity, T2DM, and other aging-related diseases. Our preliminary data further show that ALCAT1 expression is induced by ROS, triggering a vicious cycle of oxidative stress, CL depletion, and mitochondrial dysfunction. Consequently, we demonstrate that targeted deletion of ALCAT1 in mice ameliorates diet-induced obesity (DIO) and its related metabolic complications. 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 mitochondrial GTPase required for mitochondrial fusion, linking oxidative stress by ALCAT1 to defective mitochondrial quality control process. Based on these new preliminary data, we hypothesize that CL remodeling by ALCAT1 causes mitochondrial dysfunction in DIO by impairing mitochondrial fusion. We will test this hypothesis in mice with targeted deletion of MFN2 and in ob/ob mice to identify molecular mechanisms by which ALCAT1 regulates mitochondrial fusion, fission, and mitophagy. We will also determine whether ALCAT1 deficiency will prevent obesity and insulin resistance in ob/ob mice. Results from the proposed studies will provide key information on targeting ALCAT1 as 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.

氧化应激和线粒体受损是引起肥胖和二型糖尿病的重要原因，但其机制仍未被完全阐述清楚。活性氧导致心磷脂(CL)发生病态重塑，心磷脂转移酶（ALCAT1）修饰CL的支链结构，导致MFN2表达降低，引起一系列的氧化应激，线粒体功能失调和胰岛素抵抗,是肥胖和二型糖尿病发生发展的新视角。申请者首先发现并建立了ALCAT1全身敲除小鼠模型，并提出ALCAT1和肥胖和二型糖尿病发生发展相关，新近相继发现ALCAT1在肥胖及糖尿病进程中的调控作用，与氧化应激及CL重塑有关，本项目拟在原有特色的基础上，建立MFN2/ALCAT1双基因敲除小鼠模型,高脂饮食,观察ALCAT1对线粒体的融合和分裂的影响；建立ob/ob/ALCAT1双基因敲除小鼠模型，研究ALCAT1对线粒体自噬的作用机制，揭示ALCAT1敲除对肥胖和糖尿病线粒体保护的新功能，阐明ALCAT1是基于线粒体功能调节、研发多潜能代谢疾病防治的新靶标。

线粒体受损是引起肥胖和二型糖尿病的重要原因。心磷脂转移酶（ALCAT1）修饰心磷脂的支链结构，引起线粒体功能失调和胰岛素抵抗。申请者首先发现并建立了ALCAT1全身敲除小鼠模型，并提出ALCAT1和肥胖与二型糖尿病发生发展相关。本项目在原有特色基础上，构建ALCAT1/ob/ob双基因敲除小鼠模型，分析ALCAT1对其体重、肝脏糖脂代谢的影响，揭示ALCAT1敲除对肥胖和糖尿病线粒体保护的新功能。