Gegg, ME;
Cooper, JM;
Schapira, AHV;
Taanman, JW;
(2009)
Silencing of PINK1 Expression Affects Mitochondrial DNA and Oxidative Phosphorylation in DOPAMINERGIC Cells.
PLOS ONE
, 4
(3)
, Article e4756. 10.1371/journal.pone.0004756.
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Abstract
Background: Mitochondrial dysfunction has been implicated in the pathogenesis of Parkinson's disease (PD). Impairment of the mitochondrial electron transport chain (ETC) and an increased frequency in deletions of mitochondrial DNA (mtDNA), which encodes some of the subunits of the ETC, have been reported in the substantia nigra of PD brains. The identification of mutations in the PINK1 gene, which cause an autosomal recessive form of PD, has supported mitochondrial involvement in PD. The PINK1 protein is a serine/threonine kinase localized in mitochondria and the cytosol. Its precise function is unknown, but it is involved in neuroprotection against a variety of stress signalling pathways.Methodology/Principal Findings: In this report we have investigated the effect of silencing PINK1 expression in human dopaminergic SH-SY5Y cells by siRNA on mtDNA synthesis and ETC function. Loss of PINK1 expression resulted in a decrease in mtDNA levels and mtDNA synthesis. We also report a concomitant loss of mitochondrial membrane potential and decreased mitochondrial ATP synthesis, with the activity of complex IV of the ETC most affected. This mitochondrial dysfunction resulted in increased markers of oxidative stress under basal conditions and increased cell death following treatment with the free radical generator paraquat.Conclusions: This report highlights a novel function of PINK1 in mitochondrial biogenesis and a role in maintaining mitochondrial ETC activity. Dysfunction of both has been implicated in sporadic forms of PD suggesting that these may be key pathways in the development of the disease.
| Type: | Article |
|---|---|
| Title: | Silencing of PINK1 Expression Affects Mitochondrial DNA and Oxidative Phosphorylation in DOPAMINERGIC Cells |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1371/journal.pone.0004756 |
| Publisher version: | http://dx.doi.org/10.1371/journal.pone.0004756 |
| Language: | English |
| Additional information: | © 2009 Gegg et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This work was supported by grants from the Parkinson's Disease Society of the United Kingdom (4071) and the Bachmann-Strauss Dystonia and Parkinson Foundation, Inc. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/192443 |
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