Spatio-temporal assembly of respiratory chain complexes RCCs in mitochondrial fusion and fission dynamics

线粒体是高等非绿色真核生物的生物能细胞器。它们提供了细胞能量货币——ATP的绝大部分。ATP是由五种膜蛋白复合物协同作用产生的。它包括在氧化还原链中对底物的逐步氧化，并偶联在膜上产生质子梯度，为ATP合成提供电化学能量，这是最后一步。然而，这种能源生产的美好实现面临着一些挑战，并且对扰动很敏感。呼吸链平衡反应的扭曲不仅会对线粒体功能产生严重后果，而且会对细胞命运产生严重影响。线粒体损伤与神经退行性疾病的发生密切相关，在衰老过程中起着重要作用。为了保持线粒体的良好性能，建立了几个质量控制水平。线粒体的融合和裂变在其中起着重要的作用。粗略地说，它使线粒体化合物重新混合，并有助于分离功能失调的线粒体，以便通过线粒体自噬进一步消除。重要的是，导致细胞不同区域或单个线粒体内功能异质性发展的分子机制尚不清楚。线粒体的特殊超微结构、不寻常的细胞器动力学和呼吸链复合物的特殊性质，这些超复杂结构的组合显示出一种综合的相互作用，增加了另一个层次的复杂性。我们对这一具有挑战性的领域的贡献是对呼吸链组织的时空解剖。在我们的项目中，我们旨在了解细胞膜结构、蛋白质分布和功能性能之间的密切关系。我们观察到，由于结构/功能微区隔，呼吸链复合体在线粒体融合和裂变动力学过程中的再混合受到限制，并导致局部异质性。为了揭示这是如何演变的，以及它对质量控制和细胞健康有什么影响，我们将在各种条件下剖析呼吸链的组织。通过使用高度先进的实时成像技术，结合丰富的分子生物学，我们希望获得线粒体生物能量系统是如何时空和功能组织的基本理解。在神经退行性疾病线粒体衰竭的背景下，这将提供线粒体质量控制如何受到质疑和维持的新信息。

Mitochondria are the bioenergetic cell organelles of higher non-green eukaryotes. They provide the vast majority of ATP, the cellular energy currency. ATP is generated by the concerted action of five membrane protein complexes. It involves the step-wise oxidation of substrates in a redox-chain cou-pled to the generation of a proton gradient across the membrane, which provides the electrochemical energy for ATP synthesis is the last step. This beautiful realization of energy production bears several challenges, though, and is sensitive to perturbance. Distortion of the balanced reactions of the res-piratory chain has severe consequences not only for mitochondrial function but for the cellular fate in general. Mitochondrial impairment is closely associated with the development of neuro-degenerative diseases and plays an important role in the process of aging. To keep mitochondria in good perfor-mance, several quality control levels are established. Mitochondrial fusion and fission plays an im-portant role in this. Roughly, it enables the re-mixing of mitochondrial compounds and helps to sepa-rate dysfunctional mitochondria for further elimination by mitophagy. Importantly, the molecular mechanisms leading to the development of functional heterogeneity in different regions of a cell or within single mitochondria are poorly understood. The peculiar ultrastructure of mitochondria, the unu-sual organelle dynamics and the specific properties of the respiratory chain complexes which assem-bly in supercomplex structures show an integrate interplay that adds another level of complexity. Our contribution to this challenging area is the spatio-temporal dissection of the organization of the res-piratory chain. In our project we aim to understand the intimate relation between inner membrane archi-tecture, protein distribution and functional performance. We observed that owing to the structur-al/functional microcompartmentation, re-mixing of respiratory chain complexes during mitochondrial fusion and fission dynamics is limited and results in local heterogeneity. To unravel, how this evolves and what consequences it has for quality control and cellular health, we will dissect the organization of the respiratory chain under various conditions. By use of highly advanced live imaging techniques in combination with ample molecular biology we hope to gain a fundamental understanding how the mitochondrial bioenergetic system is spatio-temporally and functionally organized. In the context of mitochondrial failure in neuro-degenerative diseases this will provide new information how mitochon-drial quality control is contested and - maintained.