Dynamic regulation of the modular assembly of the mitochondrial respiratory chain

线粒体呼吸链模块化组装的动态调节

• 批准号: 504289590
• 负责人: Professorin Dr. Friederike-Nora Vögtle
• 金额: --
• 依托单位: Zentrum für Molekulare Biologie (ZMBH)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/504289590?language=en
• 关键词: Dynamic; regulation; modular; assembly; mitochondrial

The mitochondrial respiratory chain plays a central role in cellular energy metabolism by generating ATP through the process of oxidative phosphorylation. Several proteins and diverse co-factors build up the individual respiratory chain complexes that further assemble into so called supercomplexes. The activity of these complexes is adapted to the metabolic needs of the cell. Several assembly factors are required for the biogenesis of the individual complexes and assembly of the supercomplexes. Defects during the biogenesis or in the activity of the respiratory chain trigger increased generation of reactive oxygen species and oxidative stress and result in severe human diseases. The respiratory chain complexes also depend on the mitochondrial signature lipid Cardiolipin (CL) for their stability and can in turn effect CL subspecies distribution. Our knowledge of the molecular mechanisms dynamically regulating the assembly of complex IV and the adaptation of the supercomplexes upon changed metabolic demands is still limited. Also, a possible interplay between assembly factors and the distribution of CL subspecies has not been investigated so far. We have identified the novel mitochondrial protein Min8, which plays a role in the biogenesis of complex IV of the respiratory chain. Our preliminary data reveal that Min8 protein levels are dynamically regulated and strongly increase upon metabolic shift to respiratory growth conditions. Crosslinking analysis shows that Min8 associates with complex IV at the same position as the supercomplex assembly factors Rcf1 and Rcf2, that are constitutively expressed. Therefore, we postulate that different complex IV submodules exist and that their assembly into supercomplexes is dependent on the metabolic needs of the cell. Due to its dynamically adapting protein levels Min8 might function as central quality control that regulates the incorporation of different complex IV submodules into the supercomplexes. Furthermore, we have discovered that loss of the assembly factors Rcf1 and Rcf2 results in changes in the composition of CL subspecies and we now want to investigate a possible new role of Rcf1 and Rcf2 as lipid chaperones. We will investigate our hypotheses using the model organism S. cerevisiae.In summary, our project aims to uncover the molecular mechanisms underlying the biogenesis and regulation of different complex IV submodules and their assembly into supercomplexes. The analyses will contribute elementary to our understanding of this fundamental and highly conserved process of energy conversion within mitochondria.

线粒体呼吸链通过氧化磷酸化过程产生ATP，在细胞能量代谢中发挥核心作用。几种蛋白质和不同的辅因子建立了单独的呼吸链复合物，这些复合物进一步组装成所谓的超复合物。这些复合物的活性适应细胞的代谢需要。需要几个组装因子的生物合成的个别复合物和组装的超复合物。在生物发生或呼吸链活动中的缺陷触发活性氧和氧化应激的产生增加，并导致严重的人类疾病。呼吸链复合物的稳定性也依赖于线粒体标记脂质心磷脂（CL），进而影响CL亚种的分布。我们的知识的分子机制动态调节组装的复合物IV和适应的超复合物后，改变代谢的需求仍然是有限的。此外，组装因素和CL亚种的分布之间可能的相互作用尚未调查到目前为止。我们已经确定了新的线粒体蛋白质Min8，它在呼吸链复合物IV的生物合成中发挥作用。我们的初步数据表明，Min8蛋白水平是动态调节的，并在代谢转变为呼吸生长条件时强烈增加。交联分析表明，Min8与复合物IV在组成型表达的超复合物组装因子Rcf1和Rcf2相同的位置相关联。因此，我们假设存在不同的复合物IV子模块，并且它们组装成超复合物取决于细胞的代谢需求。由于其动态适应蛋白质水平Min8可能作为中央质量控制，调节不同的复合物IV亚模块纳入超复合物。此外，我们已经发现，损失的组装因子Rcf1和Rcf2的结果在CL亚种的组成的变化，我们现在想调查一个可能的新的作用，Rcf1和Rcf2作为脂质伴侣。我们将使用模式生物S来研究我们的假设。总之，我们的项目旨在揭示不同复合物IV子模块的生物发生和调节及其组装成超复合物的分子机制。这些分析将为我们了解线粒体内这种基本且高度保守的能量转换过程做出初步贡献。