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

Figure 1

Potential susceptibility of neurons to mitochondrial dysfunction and impaired mitochondrial turnover. (Wild type) In healthy neurons, mitochondria, prosurvival signals associated to signaling endosomes, and autophagomes enclosing damaged organelles or protein aggregates are able to travel long distances from the cell periphery to perinuclear region in the cell body, where most lysosomes are concentrated. (No transport) Disruption of microtubule network and subsequent defects on retrograde transport prevent the proper distribution of mitochondria and the efficient transport of autophagy substrates towards lysosomes for degradation, which can lead to defects in energy supply and cargos clearance by autophagy. (No mitophagy) Blockage of autophagic activity seems to be responsible for the accumulation of damaged mitochondria, toxic protein products, aggregates, and leaking autophagic vesicles, all of which have a negative effect on neuronal functioning and survival, precipitating the “dying-back”-type of axonal degeneration. (No fusion) The absence of mitochondrial fusion may result in an accumulation of damaged mitochondria or decreased healthy mitochondria at the nerve terminal. Mitochondria secondarily have defects in motility that prevent proper distribution within the axon and in the periphery. (No fission) In the absence of mitochondrial fission, most of the mitochondrial population is extensively long and interconnected, and a subset shows ultrastructural defects and dysfunction. The large mitochondria clusters within dendrites are not efficiently transported and/or engulfed by autophagosomes towards cell body for lysosomal degradation. (MT: microtubule tracks oriented along the axon with plus (+) ends distal and (−) ends proximal to the cell body).