Biochemical consequences of two clinically relevant ND-gene mutations

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.


Fig: Structure of complex I from human (A) and from T. thermophilus (B) (PDB: 5XTD and 6I0D). For simplicity, subunits and residues of the bacterial complex are named according to the E. coli nomenclature. The positions of the mutations are shown in red; a close-up of the positions environment is shown in the insets. Residues of the area of charged amino acids around D199MT-ND1/D213H and of the E-channel are shown in the right inset. Putative proton pathways are indicated with gray arrows, as well as NADH and quinone binding sites.

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.

Nuber, F., Schimpf, J., di Rago, JP. et al. Biochemical consequences of two clinically relevant ND-gene mutations in Escherichia colirespiratory complex I. Sci Rep 11, 12641 (2021).

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