Enzymatic oxygen reduction dominates overpotential-driven thermogenesis in mitochondria

Area of Science:

• Physical Chemistry
• Biophysics
• Biochemistry

Background:

• Heat dissipation in non-equilibrium redox systems is crucial but underexplored in biological enzymes.
• Mitochondrial thermogenesis is linked to proton leakage, but a clear physical mechanism is missing.
• Quantifying energy losses in catalytic reactions requires site-specific kinetic descriptors.

Purpose of the Study:

• To introduce electron transfer frequency (ETF) as a descriptor for enzymatic electron-transfer processes.
• To develop a framework modeling intracellular heat production via enzymatic overpotentials in mitochondria.
• To establish a common physical chemistry basis for energy dissipation in biological and electrochemical systems.

Main Methods:

• Introduced electron transfer frequency (ETF), analogous to turnover frequency (TOF).
• Developed a chemistry-based framework modeling heat production as Gibbs free energy dissipation through enzymatic overpotentials.
• Treated respiratory complexes as resistive kinetic steps and calibrated the model with experimental electrochemical parameters.

Main Results:

• Estimated 45-71% of cellular respiration energy is dissipated as heat.
• Identified Complex IV as the primary thermogenic site, contributing over 70% of total heat dissipation.
• Demonstrated that overpotential dissipation, not proton leakage, is a major heat generation pathway.

Conclusions:

• Overpotential dissipation is a quantifiable and major pathway for heat generation in mitochondria.
• Analytical principles of electrocatalysis can be extended to biological redox systems.
• Established a unified physical chemistry understanding of energy dissipation across biological and electrochemical systems.