Inactivation of mitochondrial MUL1 E3 ubiquitin ligase deregulates mitophagy and prevents diet-induced obesity in mice

Obesity is a growing epidemic affecting billions of people worldwide and a major risk factor for a multitude of chronic diseases and premature mortality. Accumulating evidence suggests that mitochondria have a profound role in diet-induced obesity and the associated metabolic changes, but the molecular mechanisms linking mitochondria to obesity remain poorly understood. Our studies have identified a new function for mitochondrial MUL1 E3 ubiquitin ligase, a protein known to regulate mitochondrial dynamics and mitophagy, in the control of energy metabolism and lipogenesis. Genetic deletion of Mul1 in mice impedes mitophagy and presents a metabolic phenotype that is resistant to high-fat diet (HFD)-induced obesity and metabolic syndrome. Several metabolic and lipidomic pathways are perturbed in the liver and white adipose tissue (WAT) of Mul1(-/-) animals on HFD, including the one driven by Stearoyl-CoA Desaturase 1 (SCD1), a pivotal regulator of lipid metabolism and obesity. In addition, key enzymes crucial for lipogenesis and fatty acid oxidation such as ACC1, FASN, AMPK, and CPT1 are also modulated in the absence of MUL1. The concerted action of these enzymes, in the absence of MUL1, results in diminished fat storage and heightened fatty acid oxidation. Our findings underscore the significance of MUL1-mediated mitophagy in regulating lipogenesis and adiposity, particularly in the context of HFD. Consequently, our data advocate the potential of MUL1 as a therapeutic target for drug development in the treatment of obesity, insulin resistance, NAFLD, and cardiometabolic diseases. To characterize gene profiling and assess a metabolic phenotype caused by the deletion of Mul1 in mice, standard RNA-sequencing for gene profiling expression of protein-coding sequences (mRNA) was performed using liver tissues from Mul1(+/+) and Mul1(-/-) mice on HFD (n =3 per group).Liver tissue from WT and KOanimals

肥胖已成为影响全球数十亿人的日益蔓延的公共卫生危机，同时亦是多种慢性疾病与过早死亡的主要风险因素。越来越多的研究证据表明，线粒体(mitochondria)在饮食诱导的肥胖及其相关代谢改变中发挥着关键作用，但连接线粒体与肥胖的分子机制仍有待阐明。本研究明确了线粒体MUL1 E3泛素连接酶（E3 ubiquitin ligase）——一种已知可调控线粒体动力学与线粒体自噬(mitophagy)的蛋白质——在能量代谢与脂肪生成(lipogenesis)调控中的全新功能。小鼠体内Mul1的基因敲除会抑制线粒体自噬，并表现出抵抗高脂饮食(high-fat diet, HFD)诱导肥胖与代谢综合征的代谢表型。在喂食HFD的Mul1敲除（Mul1(-/-)）小鼠的肝脏与白色脂肪组织(white adipose tissue, WAT)中，多条代谢与脂质组学通路发生紊乱，其中包括由硬脂酰辅酶A去饱和酶1(Stearoyl-CoA Desaturase 1, SCD1)介导的通路——该酶是脂质代谢与肥胖调控的关键调节因子。此外，在MUL1缺失的情况下，脂肪生成与脂肪酸氧化相关的关键酶，如乙酰辅酶A羧化酶1(acetyl-CoA carboxylase 1, ACC1)、脂肪酸合酶(fatty acid synthase, FASN)、AMP活化蛋白激酶(AMPK)与肉碱棕榈酰转移酶1(CPT1)，同样发生表达调控变化。在MUL1缺失时，这些酶的协同作用会减少脂肪储存并增强脂肪酸氧化。本研究结果凸显了MUL1介导的线粒体自噬在调控脂肪生成与体脂含量，尤其是在高脂饮食环境下的重要意义。因此，本研究数据表明MUL1可作为治疗肥胖、胰岛素抵抗、非酒精性脂肪性肝病(non-alcoholic fatty liver disease, NAFLD)与心脏代谢疾病的药物开发潜在治疗靶点。为了表征基因表达谱并评估小鼠Mul1缺失所导致的代谢表型，本研究对喂食HFD的Mul1野生型（Mul1(+/+)）与敲除型（Mul1(-/-)）小鼠的肝脏组织进行了标准RNA测序（RNA-sequencing），以分析蛋白编码序列（信使核糖核酸，mRNA）的基因表达谱，每组设置3个生物学重复。野生型（WT）与敲除型（KO）动物的肝脏组织