Mitochondrial dynamics and the control of adipose tissue thermogenesis

线粒体动力学和脂肪组织产热的控制

• 批准号: 10589825
• 负责人: Irfan J Lodhi
• 金额: $ 39万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589825
• 关键词: ATP Synthesis Pathway; Adipocytes; Adipose tissue; Adrenergic Agents; Biogenesis; Brown Fat; CRISPR/Cas technology; Data; Defect; Dietary Supplementation; Endoplasmic Reticulum; Energy Metabolism; Ethers; Fatty acid glycerol esters; Homeostasis; Image; Impairment; Knock-out; Link; Lipids; LoxP-flanked allele; Mass Spectrum Analysis; Mediating; Metabolic; Metabolic Diseases; Mitochondria; Mitochondrial DNA; Mitochondrial Membrane Protein; Molecular; Morphology; Mus; Non-Insulin-Dependent Diabetes Mellitus; Norepinephrine; OPA1 gene; Obesity; Organelles; Oxygen Consumption; Phospholipids; Phosphorylation; Plasmalogens; Play; Proteins; Public Health; Publishing; Regulation; Respiration; Role; Shapes; Site; Supplementation; Surface; Testing; Therapeutic; Thermogenesis; Tissues; Transgenic Mice; Tubular formation; Work; constriction; diet-induced obesity; effective therapy; innovation; knock-down; lipid metabolism; mitochondrial dysfunction; mitochondrial membrane; novel; obesity treatment; overexpression; peroxisome; recruit; response; superresolution microscopy; targeted treatment; uncoupling protein 1

Project Summary Therapeutic expansion or activation of brown adipose tissue (BAT) has a potential to be an effective treatment for obesity. BAT, as well as the closely-related beige fat, are characterized by their abundance of mitochondria, which are involved in thermogenesis through uncoupled respiration. In addition to the importance of mitochondrial functions, mitochondrial morphology plays a critical role in thermogenesis. Mitochondria are highly dynamic organelles that continuously undergo cycles of fission and fusion. Adrenergic stimulation-induced mitochondrial fission in BAT promotes uncoupled respiration and thermogenesis. Like mitochondria, peroxisomes are enriched in BAT. Our recently published studies indicate that peroxisomes play a critical role in thermogenesis through their ability to regulate cold-induced mitochondrial fission. The defect in mitochondrial fission and thermogenesis in mice with adipose-specific knockout of the critical peroxisomal biogenesis factor Pex16 (Pex16-AKO) could be rescued by dietary supplementation of peroxisome-derived lipids called plasmalogens. This project seeks to understand the molecular mechanism of peroxisomal regulation of mitochondrial dynamics and thermogenesis. Our preliminary data suggest that norepinephrine stimulation, which activates mitochondrial fission, promotes recruitment of peroxisomes to mitochondria. To understand the role of peroxisomes in mitochondrial dynamics, we performed protein mass spectrometry on mitochondria isolated from BAT of Pex16-AKO and control mice. TMEM135, a peroxisomal and mitochondrial membrane protein, was identified as the most dramatically decreased protein in the knockout BAT mitochondria, with no change of its levels in whole tissue lysates, suggesting that the protein is mistargeted in the absence of peroxisomes. TMEM135 expression in BAT increases with cold exposure. Its knockdown in brown adipocytes results in tubular mitochondria, while the overexpression promotes mitochondrial fragmentation. We hypothesize that peroxisome- mitochondria membrane contacts regulate mitochondrial localization of TMEM135 in a plasmalogen-dependent manner and that TMEM135 mediates mitochondrial fission to promote thermogenesis. We propose three specific aims to test this hypothesis. The first aim will define the role of TMEM135 in mitochondrial dynamics and function in brown adipocytes. The second aim will determine if TMEM135 overexpression in mice promotes energy expenditure through increased BAT mitochondrial fission and if it rescues thermogenesis in Pex16-AKO mice. The last aim focuses on understanding the role of TMEM135 in mitochondrial dynamics, thermogenesis, adiposity, and metabolic homeostasis using mice with adipose-specific knockout of TMEM135. Overall, this project has the potential to identify a novel organelle interaction regulating mitochondrial division, characterized by recruitment of peroxisomes to mitochondria, perhaps leading to new potential targets for therapeutic activation of BAT.

项目摘要 棕色脂肪组织（BAT）的治疗膨胀或激活具有有效治疗 肥胖。蝙蝠以及与密切相关的米色脂肪的特征是它们丰富的线粒体， 通过未偶联的呼吸参与热生成。除了重要的 线粒体功能，线粒体形态在热发生中起关键作用。线粒体高度 动态细胞器不断发生裂变和融合周期。肾上腺素能刺激引起的 蝙蝠中的线粒体裂变可促进未偶联的呼吸和热发生。像线粒体一样 过氧化物酶体富含蝙蝠。我们最近发表的研究表明，过氧化物酶体起关键作用 通过调节冷诱导的线粒体裂变的能力在热发生中。线粒体缺陷 临界过氧化物酶体生物发生因子的脂肪特异性敲除小鼠的裂变和热发生 可以通过补充过氧化物酶体衍生的脂质来挽救PEX16（PEX16-AKO） 血浆元。该项目旨在了解过氧化物酶体调节的分子机制 线粒体动力学和热发生。我们的初步数据表明去甲肾上腺素刺激，这是 激活线粒体裂变，促进过氧化物组募集到线粒体。了解 线粒体动力学中的过氧化物酶体，我们在从中分离的线粒体上进行了蛋白质质谱法 PEX16-AKO和对照小鼠的蝙蝠。 TMEM135是一种过氧化物酶体和线粒体膜蛋白，是 在基因敲除蝙蝠线粒体中被确定为蛋白质最大的蛋白质，没有变化 整个组织裂解物的水平，表明该蛋白在没有过氧化物酶体的情况下被误解。 TMEM135在蝙蝠中的表达随着冷暴露而增加。它在棕色脂肪细胞中的敲低导致管状 线粒体，而过表达促进线粒体碎片。我们假设过氧化物酶体 - 线粒体膜触点调节TMEM135在等离生原依赖性的线粒体定位 TMEM135的方式介导了线粒体裂变以促进热发生。我们提出了三个特定的 旨在检验这一假设。第一个目标将定义TMEM135在线粒体动力学和功能中的作用 在棕色脂肪细胞中。第二个目标将确定小鼠中的TMEM135过表达是否促进能量 通过增加蝙蝠线粒体裂变的支出，并在PEX16-AKO小鼠中挽救热发生。 最后一个目的是了解TMEM135在线粒体动力学，热生成，，， 使用小鼠具有TMEM135的脂肪特异性敲除小鼠的肥胖性和代谢稳态。总体而言，这 项目有可能识别一种新型的细胞器相互作用，以调节线粒体的特征 通过将过氧化物酶体募集到线粒体，可能导致了新的潜在靶标的治疗靶标 蝙蝠。