The interplay of neuronal mitochondrial dynamics and bioenergetics: implications for Parkinson's disease

Abstract

The dynamic properties of mitochondria (mitochondrial fission, fusion, transport biogenesis and degradation) are critical for neuronal function and health, and dysregulation of mitochondrial dynamics has been increasingly linked to the pathogenesis of Parkinson's disease (PD). Mitochondrial dynamics and bioenergetics are interconnected, and this is of particular importance in neurons, which have a unique bioenergetic profile due to their energetic dependence on mitochondria and specialized, compartmentalized energetic needs. In this review, we summarize the interplay of mitochondrial dynamics and bioenergetics, and its particular relevance for neurodegeneration. Evidence linking dysregulation of mitochondrial dynamics to PD is presented from both toxin and genetic models, including newly emerging details of how PD-relevant genes PTEN-induced kinase 1 (PINK1) and Parkin regulate fission, fusion, mitophagy and transport. Finally, we discuss how neuronal bioenergetics may impact PD-relevant regulation of mitochondrial dynamics, and possible implications for understanding the role of mitochondrial dynamics in PD.

FIGURE 1. Mitochondrial PINK1-Parkin Pathway Activation and Action

Following a depolarizing insult, mitochondrial import is inhibited, allowing for the accumulation of full-length PINK1 on the outer mitochondrial membrane (OMM). This triggers translocation of cytosolic Parkin to the mitochondrial outer membrane through an unknown mechanism (blue line). Upon translocation, Parkin begins to ubiquitinate substrates on the OMM, including VDAC1, Miro, and mitofusins (Mfn), which are subsequently targeted for proteasomal degradation. Degradation of Miro also blocks the assembly of the Miro-Milton-Kinesin (KIF5) complex for anterograde transport. These events are then followed by targeting of the depolarized mitochondrion for mitophagy. Information summarized from references detailed in text.

FIGURE 2. Effects of Dysfunction of Mitochondrial Dynamics in Neurons

The top panel diagrams a normally functioning neuron, outlining specific compartmentalized aspects of mitochondrial dynamics in the cell body, dendritic regions, and axons/synapses. The bottom panel shows potential neuropathologic consequences of localized dysregulation of mitochondrial dynamics.