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

• Applicant: Professorin Dr. Karin Busch
• Subject Area: Cell Biology ; Biochemistry
• Term: from 2007 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 41407014

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.

• DFG Programme: Research Grants