3.D.1.3.1
NADH Dehydrogenase, NDH (Baradaran et al. 2013).  The x-ray structures of various complexes have been solved, and a coupling mechanism involving long range conformational changes has been proposed (Sazanov et al. 2013). The complex includes 16 subunits with nine iron-sulfur clusters, reduced by electrons from NADH. Employing the latest crystal structure of T. thermophilus complex I, Gupta et al. 2020 used microsecond-scale molecular dynamics simulations to study the chemo-mechanical coupling between redox changes of the iron-sulfur clusters and conformational transitions across complex I. The simulations revealed the molecular design principles linking redox reactions to quinone turnover and proton translocation in complex I. Using a zebrafish model of TB infection, Roca et al. 2022 found that tumor necrosis factor (TNF) induces reverse electron transport (RET) in mitochondrial complex I. This in turn drives the production of mitochondrial reactive oxygen species (mROS), causing macrophage necrosis. The complex I inhibitor metformin could be repurposed to inhibit TNF-induced mROS and necrosis in infected zebrafish and human macrophages, suggesting that this common antidiabetes drug may also be a useful adjunct therapy for TB (Roca et al. 2022).