Figure 2. Potential susceptibility of neurons to impaired mitochondrial dynamics.

The unique energy demands of axons and nerve terminals, particularly those of the dopaminergic nigrostriatal pathway, are dependent on proper mitochondrial distribution and function. At the terminus, mitochondria are critical for calcium buffering and energy for maintaining the vesicular pool. Environmental and genetic factors may contribute to increased mitochondrial and oxidative stress, impacting mitochondrial function, fission and fusion, transport, and perhaps even mitochondrial maintenance systems (red connectors). The dopaminergic neurons of the substantia nigra are known to have increased oxidative stress, due in part to the oxidative nature of the neurotransmitter dopamine (DA). Mitochondrial dysfunction also has the potential to set up a vicious cycle of increased oxidative stress, through production of reactive oxygen species (ROS) and decreased energy availability (red arrows). B. Altered or disrupted mitochondrial dynamics, which may result in an accumulation of damaged mitochondria or decreased distribution of healthy mitochondria at the nerve terminal and within the axon, may ultimately lead to stress and terminal loss, propagating back to the cell body.