DRP1-mediated mitochondrial fission and mitophagy in Parkinsons disease

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra of the brain, leading to motor and non-motor symptoms. Accumulating evidence suggests that mitochondrial dysfunction plays a critical role in the pathogenesis of PD. Mitochondria are dynamic organelles that undergo fission and fusion to maintain their function and quality. Mitochondrial fission is mediated by dynamin-related protein 1 (DRP1), a GTPase that translocates from the cytosol to the outer mitochondrial membrane (OMM) in response to various signals. DRP1 recruitment to the OMM is regulated by post-translational modifications, such as phosphorylation, ubiquitination, and SUMOylation. Once DRP1 is anchored to the OMM, it assembles into a ring-like structure that constricts the membrane and leads to mitochondrial fragmentation.

Recent studies have shown that aberrant DRP1-mediated mitochondrial fission is associated with PD pathogenesis. Mutations in genes encoding proteins involved in mitochondrial dynamics, such as PINK1, Parkin, and DJ-1, have been identified in familial forms of PD. These genes play critical roles in mitophagy, a process by which damaged or dysfunctional mitochondria are selectively removed by autophagy. Mitophagy is regulated by the PINK1-Parkin pathway, which involves the recruitment of Parkin to depolarized mitochondria and the ubiquitination of OMM proteins. This leads to the recruitment of autophagy receptors, such as p62 and NDP52, which bridge the mitochondria to the autophagosome for degradation.

Recent studies have shown that DRP1-mediated mitochondrial fission is required for efficient mitophagy in response to depolarization or oxidative stress. DRP1-dependent mitochondrial fission promotes the segregation of damaged mitochondria from the mitochondrial network, allowing them to be targeted for mitophagy. DRP1 also interacts with the autophagy machinery, promoting the formation of autophagosomes around depolarized mitochondria. Inhibition of DRP1-mediated mitochondrial fission impairs mitophagy and leads to the accumulation of damaged mitochondria in cells. These findings suggest that DRP1-mediated mitochondrial fission is a critical step in the clearance of damaged mitochondria and the maintenance of mitochondrial quality control.

In summary, DRP1-mediated mitochondrial fission and mitophagy play crucial roles in PD pathogenesis. Aberrant DRP1 activation and impaired mitophagy lead to the accumulation of damaged mitochondria, which contribute to neuronal dysfunction and death in PD. Targeting DRP1-mediated mitochondrial fission and mitophagy may provide novel therapeutic strategies for PD and other neurodegenerative diseases