Figure 8. Schematic representation of the pathogenic cascade in neurodegenerative diseases due to AFG3L2 deficiency.

Upon AFG3L2 deficiency, mitochondria become dysfunctional due to impaired mitochondrial protein synthesis and reduced assembly of respiratory chain subunits. The resulting respiratory impairment causes, on one side, stress-induced fragmentation of mitochondria via OMA1 activation and, on the other side, increased ROS production. ROS trigger a pathogenic cascade leading to hyperphosphorylation of tau, which in turn can affect mitochondrial anterograde transport. ROS may also hinder transport via some other yet uncharacterized mechanism. Defects in anterograde transport of mitochondria lead to depletion of mitochondria in axons and neurodegeneration.