Mitochondrial cell biology: Understanding the molecular mechanisms and functions of mitochondrial dynamics and membrane contact sites

线粒体细胞生物学：了解线粒体动力学和膜接触位点的分子机制和功能

• 批准号: MC_UU_00028/5
• 负责人: Julien Prudent
• 金额: $ 409.53万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Intramural
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MC_UU_00028%2F5
• 关键词: Mitochondrial; cell; biology; Understanding; molecular

Mitochondria form a dynamic and connected network, which is constantly remodelled by cycles of membrane fission and fusion. These dynamic transitions are not only required to ensure a proper mitochondrial function but also to respond to cellular needs and adapt to the metabolic state of the cell. To execute cellular functions, mitochondria also establish membrane contact sites with other organelles, including the endoplasmic reticulum, peroxisomes and lysosomes. These organelle membrane contact sites are hotspots for metabolites flux and tightly regulate mitochondrial architecture. While defects in mitochondrial morphology or contact sites have been associated with human diseases, the molecular mechanisms linking mitochondrial membrane remodelling to cell fate decisions are poorly understood. The Prudent group focusses on understanding the mechanisms regulating membrane dynamics and remodelling, how they influence cellular functions and govern cell fate decisions. In our first research aim, we employ state-of-the-art to identify and functionally characterise new proteins regulating mitochondrial morphology and mitochondria-organelle contact sites, and how they govern cell fate decisions. Our second aim of research is to elucidate how mitochondrial membrane remodelling regulates mitochondrial (mt)DNA quality control and modulates cytosolic mtDNA release driving inflammation to control cellular homeostasis.

线粒体形成一个动态连接的网络，通过膜裂变和融合的循环不断重塑。这些动态转变不仅需要确保线粒体的正常功能，而且还需要响应细胞的需要和适应细胞的代谢状态。为了执行细胞功能，线粒体还与其他细胞器建立膜接触位点，包括内质网、过氧化物酶体和溶酶体。这些细胞器膜接触部位是代谢物通量的热点，并密切调节线粒体结构。虽然线粒体形态或接触部位的缺陷与人类疾病有关，但将线粒体膜重塑与细胞命运决定联系起来的分子机制却知之甚少。审慎小组专注于了解调节膜动力学和重塑的机制，它们如何影响细胞功能和控制细胞命运的决定。在我们的第一个研究目标中，我们采用最先进的技术来识别和功能表征调节线粒体形态和线粒体-细胞器接触位点的新蛋白质，以及它们如何控制细胞命运决定。我们的第二个研究目标是阐明线粒体膜重塑如何调节线粒体（mt）DNA质量控制和调节细胞质mtDNA释放驱动炎症来控制细胞稳态。

项目成果

A mouse model of human mitofusin-2-related lipodystrophy exhibits adipose-specific mitochondrial stress and reduced leptin secretion.

• DOI: 10.7554/elife.82283
• 发表时间: 2023-02-01
• 期刊: eLife
• 影响因子: 7.7
• 作者: Mann JP;Duan X;Patel S;Tábara LC;Scurria F;Alvarez-Guaita A;Haider A;Luijten I;Page M;Protasoni M;Lim K;Virtue S;O'Rahilly S;Armstrong M;Prudent J;Semple RK;Savage DB
• 通讯作者: Savage DB

mtFociCounter for automated single-cell mitochondrial nucleoid quantification and reproducible foci analysis.

• DOI: 10.1093/nar/gkad864
• 发表时间: 2023-11-27
• 期刊: Nucleic acids research
• 影响因子: 14.9

AMPK-dependent phosphorylation of MTFR1L regulates mitochondrial morphology.

MTFR1L的AMPK依赖性磷酸化调节线粒体形态。

• DOI: 10.1126/sciadv.abo7956
• 发表时间: 2022-11-11
• 期刊: Science advances
• 影响因子: 13.6