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Biochemical consequences of two clinically relevant ND-gene mutations in Escherichia coli respiratory complex I

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Nuber, Franziska 
Schimpf, Johannes 
di Rago, Jean-Paul 
Tribouillard-Tanvier, Déborah 
Procaccio, Vincent 


Abstract: NADH:ubiquinone oxidoreductase (respiratory complex I) plays a major role in energy metabolism by coupling electron transfer from NADH to quinone with proton translocation across the membrane. Complex I deficiencies were found to be the most common source of human mitochondrial dysfunction that manifest in a wide variety of neurodegenerative diseases. Seven subunits of human complex I are encoded by mitochondrial DNA (mtDNA) that carry an unexpectedly large number of mutations discovered in mitochondria from patients’ tissues. However, whether or how these genetic aberrations affect complex I at a molecular level is unknown. Here, we used Escherichia coli as a model system to biochemically characterize two mutations that were found in mtDNA of patients. The V253AMT-ND5 mutation completely disturbed the assembly of complex I, while the mutation D199GMT-ND1 led to the assembly of a stable complex capable to catalyze redox-driven proton translocation. However, the latter mutation perturbs quinone reduction leading to a diminished activity. D199MT-ND1 is part of a cluster of charged amino acid residues that are suggested to be important for efficient coupling of quinone reduction and proton translocation. A mechanism considering the role of D199MT-ND1 for energy conservation in complex I is discussed.


Funder: Albert-Ludwigs-Universität Freiburg im Breisgau (1016)


Article, /631/45/607/1167, /631/45/607/1168, /631/45/612/1237, article

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Scientific Reports

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Nature Publishing Group UK
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (176154)
Deutsche Forschungsgemeinschaft (278002225/RTG 2202)