Understanding and Modulating Respiratory Complex I Activity in Mitochondrial Disease - what is the pathophysiology underlying complex I deficiency?

Mitochondrial complex I (CI) dysfunction underlies devastating pediatric disorders such as Leigh Syndrome and contributes to age-associated neurodegeneration, including Parkinson’s and Alzheimer’s disease. Surprisingly, hypoxia has emerged as a potential intervention: lowering oxygen availability rescues C. elegans and mouse CI mutants, even reversing neurodegeneration in a mouse model of Leigh syndrome. Recent genetic screens in C. elegans performed by Meisel et al identified “hypoxia-mimetic” mutations in CI subunits that restore electron flow, as well as “hypoxia-resistant” mutations in the quinone-binding pocket that block rescue. However, due to lack of structural data the molecular mechanisms by which hypoxia and these mutations rescue CI function remain unknown. A recent structure-based hypothesis from our lab points to a CI assembly intermediate that accumulates in the mouse Ndufs4 KO and may drain electrons and H+ from the electron transport chain (ETC) in an oxygen dependent manner. Our central hypothesis is that hypoxia and hypoxia-mimetic mutations stabilize specific conformations or assembly states of CI supercomplexes that reduce pathological reverse electron transfer (RET) and restore forward electron flow. You would use organelle isolation, membrane protein purification, structural characterization by single-particle cryogenic electron microscopy (cryoEM) and functional characterization using spectroscopic enzyme activity assays and respirometry, to characterize respiratory supercomplexes from key model organisms and mutants. Only extremely dedicated and driven students with excellent oral and written communication skills should apply.