Analysis of the role of mitochondrial morphology in autophagy
Year: 2016
Type: article
Abstract: PARK2 gene encodes for an E3 ubiquitin ligase called Parkin. Loss-of-function mutations in this gene cause early onset of Parkinson’s disease, a neurodegenerative disorder of unknown etiology. The role of Parkin in neuron maintenance is still unknown, however it has been linked to the regulation of mitochondria dynamic. Recent works show that Parkin is selectively recruited to dysfunctional mitochondria, where it mediates their elimination via autophagy. Parkin translocation and Parkin-mediated autophagy depend on the Serine/Threonine-protein kinase PINK1 (PTEN-induced putative kinase 1), which is selectively stabilized on dysfunctional mitochondria where it recruits Parkin. However, it remains unknown which cellular signals or covalent modifications directly regulate Parkin translocation. Confocal microscopy of EYFP-Parkin transfected MEFs shows that Parkin has a cytoplasmic localization. After treatment with the mitochondrial uncoupling agent Carbonyl cyanide m-chlorophenyl hydrazine (CCCP), Parkin appears as spots that co-localize with mitochondria. We found that pretreatment with the Ca2+ selective chelator BAPTA completely blocked Parkin translocation. We also found that inhibition of Ca2+ dependent phosphatase Calcineurin A (CnA) impaired Parkin recruitment and that CaN constitutive active expression was able to induce Parkin translocation per se, independently from PINK1. In accordance to the in vitro data, we showed that in the Drosophila fruit fly, Calcineurin constitutive active expression is able to rescue the climbing ability of a PINK1 in vivo model of Parkinson’s Disease.
Author: Alice Nardin
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2560107331