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）的治疗性扩张或激活有可能成为一种有效的治疗方法 治疗肥胖症BAT以及与之密切相关的米色脂肪的特点是它们富含线粒体， 它们通过非偶联呼吸参与产热。除了重要性之外， 线粒体功能，线粒体形态在产热中起着关键作用。线粒体高度 不断经历裂变和融合循环的动态细胞器。肾上腺素能刺激诱导 BAT中的线粒体分裂促进解偶联呼吸和产热。像线粒体一样， 过氧化物酶体富含BAT。我们最近发表的研究表明，过氧化物酶体发挥关键作用， 通过调节冷诱导的线粒体分裂的能力在产热中起作用。线粒体的缺陷 脂肪特异性敲除关键过氧化物酶体生物发生因子小鼠的分裂和产热 Pex 16（Pex 16-AKO）可以通过膳食补充过氧化物酶体衍生的脂质（称为 缩醛磷脂该项目旨在了解过氧化物酶体调节的分子机制， 线粒体动力学和产热。我们的初步数据表明，去甲肾上腺素刺激， 激活线粒体分裂，促进过氧化物酶体向线粒体的募集。为了理解 在线粒体动力学的过氧化物酶体，我们进行了蛋白质质谱分离的线粒体， Pex 16-AKO和对照小鼠的BAT。TMEM 135是一种过氧化物酶体和线粒体膜蛋白， 被鉴定为敲除BAT线粒体中最显著减少的蛋白质，其 在整个组织裂解物的水平，表明蛋白质是错误的过氧化物酶体的情况下。 BAT中的TMEM 135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片段化。我们假设过氧化物酶体- 线粒体膜接触调节TMEM 135的线粒体定位， TMEM 135介导线粒体分裂以促进产热。我们提出三个具体的 旨在验证这一假设。第一个目标是确定TMEM 135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TMEM 135的过表达是否促进能量消耗。 在Pex 16-AKO小鼠中，通过增加BAT线粒体分裂来消耗能量，并且如果它拯救产热。 最后一个目的是了解TMEM 135在线粒体动力学，产热， 肥胖和代谢稳态。总体而言，这 该项目有可能确定一种调节线粒体分裂的新型细胞器相互作用，其特征在于 通过将过氧化物酶体募集到线粒体，可能导致治疗激活的新的潜在靶点 的BAT。