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MITRAC Report Summary

Project ID: 339580
Funded under: FP7-IDEAS-ERC
Country: Germany

Mid-Term Report Summary - MITRAC (Mitochondrial translational regulation coupled to respiratory chain assembly and protein import)

Mitochondria built their oxidative phosphorylation system from subunits of dual genetic origin. The question as to how the assembly process of these intricate membrane protein complexes is regulated and how the supply of subunits derived from cytosolic and mitochondrial translation are adjusted against each other represents a central challenge in molecular biology with far reaching implications for biomedical research.
Here we aim to understand the early steps of the assembly process of the respiratory chain complex IV (cytochrome c oxidase) and to answer the long standing question if a link between biogenesis pathway and translation on mitochondrial ribosomes exists in human mitochondria. To this end, we have purified and dissected assembly intermediates of the core subunit COX1 termed MITRAC complexes. Our analyses have identified proteins that participate in COX1 biogenesis and affect translation on mitochondrial ribosomes by a yet undefined mechanism. In addition, the purification regime has allowed us to define new MITRAC factors in the biogenesis pathway as well as a quality control checkpoint directing intermediates towards turnover or further along the assembly pipeline. Among factors that lead to an accumulation of MITRAC intermediates, we identified a metallochaperone that mediates copper insertion into COX2 and when defective causes cardiomyopathy in human. Since defects in complex IV assembly cause a heterogeneous group of rare neuromuscular and cardiac disorders we will analyze how defective assembly and translational regulation affect tissue function. Therefore, we currently generate new models for physiological analyses. The analyses proposed here will not only provide unexpected new insights into the assembly mechanism of the OXPHOS system, its regulation, and the pathophysiology of its malfunction but moreover will shape our concept on how two genetically independent systems cooperate to build a functional metabolic pathway able to respond to energetic requirements and challenges.

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