Mitochondrial morphology governs ATP production rate

Area of Science:

• Biophysics
• Neuroscience
• Biochemistry

Background:

• Neurons require substantial energy for synaptic transmission and homeostasis, primarily met by mitochondrial oxidative phosphorylation.
• Accurate models of mitochondrial ATP production are essential for understanding neuronal metabolic demands.

Purpose of the Study:

• To develop a thermodynamically consistent model of ATP production in mitochondria.
• To incorporate physical plausibility by ensuring detailed balance and explicitly defining reaction rate dependencies on physiological parameters.
• To investigate the limiting factors of ATP availability in the cytosol under various conditions.

Main Methods:

• Developed a thermodynamically consistent model of mitochondrial ATP production.
• Ensured reaction rate constants satisfy detailed balance.
• Incorporated thermodynamic considerations for reaction rate dependencies on membrane potential, pH, and substrate concentrations.
• Performed simulations exploring parameter regimes and spatial simulations with 3D mitochondrial reconstructions.

Main Results:

• The model satisfies detailed balance and thermodynamic constraints, ensuring physical plausibility.
• Simulations indicate that ATP production, rather than export, is the rate-limiting step for cytosolic ATP availability under the studied conditions.
• Spatial simulations linked mitochondrial morphology to cytosolic ATP production rates.

Conclusions:

• The developed model provides a physically plausible framework for studying mitochondrial energy metabolism in neurons.
• ATP production is identified as the bottleneck for cytosolic ATP supply in simulated neuronal conditions.
• Mitochondrial morphology influences cellular energy distribution.