Mitochondria drive autophagy pathology via microtubule disassembly: a new hypothesis for Parkinson disease

Abstract

Neurons are exquisitely dependent on quality control systems to maintain a healthy intracellular environment. A permanent assessment of protein and organelle "quality" allows a coordinated action between repair and clearance of damage proteins and dysfunctional organelles. Impairments in the intracellular clearance mechanisms in long-lived postmitotic cells, like neurons, result in the progressive accumulation of damaged organelles and aggregates of aberrant proteins. Using cells bearing Parkinson disease (PD) patients' mitochondria, we demonstrated that aberrant accumulation of autophagosomes in PD, commonly interpreted as an abnormal induction of autophagy, is instead due to defective autophagic clearance. This defect is a consequence of alterations in the microtubule network driven by mitochondrial dysfunction that hinder mitochondria and autophagosome trafficking. We uncover mitochondria and microtubule-directed traffic as main players in the regulation of autophagy in PD.

Figure 1. Model for autophagic pathology triggered by mitochondrial dysfunction in Parkinson disease. (A) In normally functioning neurons, mitochondria and autophagosomes enclosing damaged organelles or protein aggregates are able to travel long distances from the cell periphery to the perinuclear region in the cell body along the microtubule network. (B) In Parkinson disease-affected neurons, disruption of the microtubule network due to mitochondrial dysfunction and subsequent defects in retrograde/anterograde transport prevent proper distribution of mitochondria and the efficient transport of autophagosomes and autophagic substrates toward lysosomes for degradation. Deficient autophagic clearance results in accumulation of SNCA oligomers, other toxic protein products, and/or dysfunctional mitochondria, which in turn is detrimental for neuronal functioning and survival, promoting the “dying-back”-type of axonal degeneration.