Deactivation blocks proton pathways in the mitochondrial complex I.

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• Cellular respiration relies on membrane-bound redox enzymes to generate energy via proton gradients.
• Mammalian complex I is crucial for energy metabolism, converting chemical energy into an electrochemical proton gradient.

Purpose of the Study:

• To elucidate the molecular mechanisms of conformational changes in mammalian complex I during proton pumping.
• To identify key regions and residues involved in regulating proton transfer and energy transduction.

Main Methods:

• Integration of large-scale classical and quantum mechanical simulations.
• Analysis of cryo-electron microscopy data for mammalian complex I.
• Investigating conformational changes and their impact on proton transfer pathways.

Main Results:

• Complex I deactivation inhibits water-mediated proton transfer, decoupling energy transduction.
• A gating region at the ND1/ND3/ND4L/ND6 interface modulates proton transfer via conformational changes.
• Mutations in this region are linked to human mitochondrial disorders.

Conclusions:

• Transmembrane helix conformational changes regulate proton transfer dynamics through wetting/dewetting transitions.
• The identified gating region provides functional insight into mammalian respiratory complex I activity.
• Findings illuminate the molecular basis of energy transduction and its disruption in mitochondrial diseases.