Mitochondrial dynamics in Parkinson's disease

Abstract

The unique energy demands of neurons require well-orchestrated distribution and maintenance of mitochondria. Thus, dynamic properties of mitochondria, including fission, fusion, trafficking, biogenesis, and degradation, are critical to all cells, but may be particularly important in neurons. Dysfunction in mitochondrial dynamics has been linked to neuropathies and is increasingly being linked to several neurodegenerative diseases, but the evidence is particularly strong, and continuously accumulating, in Parkinson's disease (PD). The unique characteristics of neurons that degenerate in PD may predispose those neuronal populations to susceptibility to alterations in mitochondrial dynamics. In addition, evidence from PD-related toxins supports that mitochondrial fission, fusion, and transport may be involved in pathogenesis. Furthermore, rapidly increasing evidence suggests that two proteins linked to familial forms of the disease, parkin and PINK1, interact in a common pathway to regulate mitochondrial fission/fusion. Parkin may also play a role in maintaining mitochondrial homeostasis through targeting damaged mitochondria for mitophagy. Taken together, the current data suggests that mitochondrial dynamics may play a role in PD pathogenesis, and a better understanding of mitochondrial dynamics within the neuron may lead to future therapeutic treatments for PD, potentially aimed at some of the earliest pathogenic events.

Figure 1. The emerging role for parkin and PINK1 in mitochondrial dynamics and homeostasis

A. Mounting evidence suggests that parkin operates downstream of PINK1 in a common pathway to regulate mitochondrial dynamics. In many cells, it appears to promote fission and/or inhibit fusion, though fission/fusion regulatory effects may differ by cell type or cellular environment. Such regulation may involve parkin-mediated regulation of mitochondrial fission/fusion machinery, either directly or indirectly, as through protein ubiquitination. Regulation may also involve some as yet unidentified parkin-mediated regulatory or protein-interaction pathway. B. How and through what pathway PINK1 and parkin interact is not known. The specific localization of both proteins is subject to controversy. Given current evidence, PINK1 may directly interact with and recruit parkin either, i. at the mitochondrial outer membrane, ii. in the cytosol, following cleavage and/or translocation of PINK1 out of the mitochondria, or iii. within the mitochondria. Alternatively, PINK1 may act through an intermediary (grey circles) to modify and/or recruit parkin to the mitochondria. PINK1 was also shown to directly phosphorylate cytosolic parkin, recruiting it to the mitochondria (blue pathways). However, where and how parkin exerts its effects on the mitochondria, whether inside the mitochondria, at the surface, or by interacting with surface proteins (pink ovoid), is unknown. C. Parkin was recently shown to localize to depolarized mitochondria, targeting them for mitophagy. The signals that target parkin to the damaged mitochondria, however, are not known. Whether this pathway is related to the fission/fusion regulatory functions of the PINK1/parkin pathway is also not known, though mitochondrial fission was previously shown to be an apparent prerequisite for mitophagy. See text for related references. ims = intermembrane space

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.