Two hit mitochondrial-driven model of synapse loss in neurodegeneration

In healthy neurons, a mitochondrial membrane potential gradient exists whereby membrane potential is highest in the soma and decreases with distance from the nucleus. Correspondingly, distal mitochondria have more oxidative damage and slower protein import than somal mitochondria. Due to these differences, distal mitochondria have an intrinsic first stressor that somal mitochondria do not have, resulting in synaptic mitochondrial vulnerability. A second stressor may result from mutant protein expression, situational stress, or aging, exacerbating vulnerable mitochondria activating stress responses. Under these conditions, distal mitochondria release cytochrome c and mitochondrial DNA, leading to compartmentalized sub-lethal caspase-3 activation and cytokine production. In this two-hit mitochondrial-driven synaptic loss model, synapse vulnerability during neurodegeneration is explained as a superposition of pre-existing lower synaptic mitochondrial membrane potential (hit one) with additional mitochondrial stress (hit two). This two-hit mechanism occurs in synaptic mitochondria, activating signaling pathways leading to synaptic degeneration, as a potential preamble to neuronal death.