Can drugs modulating mitochondrial dynamics be translated into neuroprotection in Parkinson's disease?

Abstract

Mitochondria are dynamic and mobile organelles undergoing continuous membrane remodeling. The separating and merging processes of mitochondrial membranes are named fission and fusion respectively. Proper balance of mitochondrial dynamics is crucial for maintenance of cellular energy status. Promoted fusion improves the interconnectivity of mitochondrial network, while excessive fission causes mitochondrial fragmentation. Extensive fragmentation of mitochondria predisposes intrinsic apoptosis, but inhibition of fission machinery suppresses cell death. More lines of evidence are supporting mitochondrial abnormalities as a key contributor to various neurodegenerative diseases, while mitochondrial dynamics are disturbed prior to mitochondrial dysfunction. Parkinson’s disease (PD) is one of the most prevalent neurodegenerative diseases in the aging populations. Clinical features include motor deficits encompassing bradykinesia, postural instability, rigidity and tremor, thus ultimately lead to total immobility. Current therapies of PD are largely symptomatic, while promising curing or preventive medications are yet well established. Therefore, modulation of mitochondrial dynamics, especially for targeting at dynamic balance shift to fusion side, could be a therapeutic target for PD.

Mitochondrial division inhibitor-1 (mdivi-1) and mitochondrial fusion promoter M1 hydrazone are drugs modulating mitochondrial dynamics. Mdivi-1 inhibits fission processes, while M1 hydrazone promotes fusion processes. This study investigates the neuroprotective effects of mdivi-1 and M1 hydrazone from 6-hydroxydopamine (6-OHDA)-induced toxicity in primary cultured cortical neurons. My current results demonstrated that mdivi-1 and M1 hydrazone attenuated 6-OHDA-induced apoptosis. Furthermore, mdivi-1 and M1 hydrazone restored 6-OHDA-induced mitochondrial abnormalities such as oxidative stress and outer membrane permeabilization. These findings suggested the neuroprotective effects of mdivi-1 and M1 hydrazone. The current study provides insights into preventive and therapeutic measures of PD.