Dynamic regulation of the modular assembly of the mitochondrial respiratory chain

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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.