Mitochondrial Fusion/Fission, Transport and Autophagy in Parkinson's Disease: When Mitochondria Get Nasty

Figure 2

Rationale for the contribution of mitochondrial dysfunction to synaptic degeneration in sporadic PD. Mitochondrial dysfunction induced by a complex I defect leads to alterations in mitochondria-dependent metabolism (reduced ATP levels and decreased mitochondrial inner membrane potential). This bioenergetic failure seems to potentiate microtubule network breakdown. Subsequently, when the dynamics and functional integrity of microtubules are compromised, changes in anterograde and retrograde flux along the axon can be impaired. Cargos that are actively transported along the axon include mitochondria, autophagosomes, and proteins. Moreover, a decrease in mitochondrial membrane potential deregulates calcium homeostasis, which leads to the overactivation of calpains. Calpains are key regulators of mitochondrial fusion, since they impair Opa1 proper function. Alterations in fusion/fission events promote mitochondrial enlargement, which can impair their removal by mitophagy. Indeed, the accumulation of protein aggregates, autophagosomes, and enlarged deficient mitochondria in presynaptic termini is observed at early stages of PD. Our hypothesis implies that mitochondrial metabolism impairment could be responsible for synaptic degeneration in PD. (*Indicates that mutated or overexpressed α-synuclein could induce mitochondrial dysfunction and that loss-of-function of Parkin or/and PINK1 can deregulate mitochondrial mitophagy.)