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J Biol Chem. 2014 Oct 24;289(43):29519-30. doi: 10.1074/jbc.M114.607150. Epub 2014 Sep 12.

Short mitochondrial ARF triggers Parkin/PINK1-dependent mitophagy.

Author information

1
From the Department of Neurology and Neurosurgery and McGill Parkinson Program, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada.
2
From the Department of Neurology and Neurosurgery and McGill Parkinson Program, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada ted.fon@mcgill.ca.

Abstract

Parkinson disease (PD) is a complex neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra. Multiple genes have been associated with PD, including Parkin and PINK1. Recent studies have established that the Parkin and PINK1 proteins function in a common mitochondrial quality control pathway, whereby disruption of the mitochondrial membrane potential leads to PINK1 stabilization at the mitochondrial outer surface. PINK1 accumulation leads to Parkin recruitment from the cytosol, which in turn promotes the degradation of the damaged mitochondria by autophagy (mitophagy). Most studies characterizing PINK1/Parkin mitophagy have relied on high concentrations of chemical uncouplers to trigger mitochondrial depolarization, a stimulus that has been difficult to adapt to neuronal systems and one unlikely to faithfully model the mitochondrial damage that occurs in PD. Here, we report that the short mitochondrial isoform of ARF (smARF), previously identified as an alternate translation product of the tumor suppressor p19ARF, depolarizes mitochondria and promotes mitophagy in a Parkin/PINK1-dependent manner, both in cell lines and in neurons. The work positions smARF upstream of PINK1 and Parkin and demonstrates that mitophagy can be triggered by intrinsic signaling cascades.

KEYWORDS:

Mitochondria; Mitophagy; PTEN-induced Putative Kinase 1 (PINK1); Parkin; Parkinson Disease; smARF

PMID:
25217637
PMCID:
PMC4207970
DOI:
10.1074/jbc.M114.607150
[Indexed for MEDLINE]
Free PMC Article

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