FIGURE 3.

Hypothetical mechanisms underlying differential mitochondrial Ca²⁺ dynamics and ROS production. Neuronal or electrical stimulation-induced cytosolic Ca²⁺ transient can result in rapid Ca²⁺ influx into mitochondria, serving as a stimulant of multiple enzyme complex in OXPHOS that accelerate electron flux along the respiratory chain, leading to decreased accumulation of ubisemiquinone (UQ) and lower O₂ partial pressure. Both factors contribute to alleviated superoxide production. On the other hand, we hypothesize that a key mPTP component may have two sets of Ca²⁺ sensory structures with different Ca²⁺ affinities, resulting in distinct responses to rapid versus steady-state elevation of [Ca²⁺]_mito. Steady-state elevation of [Ca²⁺]_mito resulting from denervation or other pathological conditions may predominantly trigger the response mediated by a relatively higher affinity structure (such as the Ca²⁺ binding site within the F1 domain nucleotide binding pockets of ATP synthase), which promotes mPTP opening, enhances Cyt c release, disrupts complex III activity, and increases superoxide production. The rapid mitochondrial Ca²⁺ transients induced by motor neuron input or electrical stimulation may predominantly activate the response mediated by a relatively lower affinity Ca²⁺ responding structure, shutting down mPTP and decrease ROS production.