S-Nitrosylation of PINK1 Attenuates PINK1/Parkin-Dependent Mitophagy in hiPSC-Based Parkinson’s Disease Models
Mutations in PARK6 (PINK1) and PARK2 (Parkin) are linked to rare familial cases of Parkinson’s disease (PD). Mutations in these genes result in pathological dysregulation of mitophagy, contributing to neurodegeneration. Here, we report that environmental factors causing a specific posttranslational...
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doaj-6cbba4e38c0245ebabf9b742b039a55d2020-11-25T02:36:02ZengElsevierCell Reports2211-12472017-11-012182171218210.1016/j.celrep.2017.10.068S-Nitrosylation of PINK1 Attenuates PINK1/Parkin-Dependent Mitophagy in hiPSC-Based Parkinson’s Disease ModelsChang-Ki Oh0Abdullah Sultan1Joseph Platzer2Nima Dolatabadi3Frank Soldner4Daniel B. McClatchy5Jolene K. Diedrich6John R. Yates, III7Rajesh Ambasudhan8Tomohiro Nakamura9Rudolf Jaenisch10Stuart A. Lipton11Departments of Molecular Medicine and Neuroscience and Neuroscience Translational Center, The Scripps Research Institute, La Jolla, CA 92037, USANeurodegenerative Disease Center, Scintillon Institute, San Diego, CA 92121, USANeuroscience and Aging Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USADepartments of Molecular Medicine and Neuroscience and Neuroscience Translational Center, The Scripps Research Institute, La Jolla, CA 92037, USAWhitehead Institute for Biomedical Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USADepartments of Molecular Medicine and Neuroscience and Neuroscience Translational Center, The Scripps Research Institute, La Jolla, CA 92037, USADepartments of Molecular Medicine and Neuroscience and Neuroscience Translational Center, The Scripps Research Institute, La Jolla, CA 92037, USADepartments of Molecular Medicine and Neuroscience and Neuroscience Translational Center, The Scripps Research Institute, La Jolla, CA 92037, USANeurodegenerative Disease Center, Scintillon Institute, San Diego, CA 92121, USADepartments of Molecular Medicine and Neuroscience and Neuroscience Translational Center, The Scripps Research Institute, La Jolla, CA 92037, USAWhitehead Institute for Biomedical Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USADepartments of Molecular Medicine and Neuroscience and Neuroscience Translational Center, The Scripps Research Institute, La Jolla, CA 92037, USAMutations in PARK6 (PINK1) and PARK2 (Parkin) are linked to rare familial cases of Parkinson’s disease (PD). Mutations in these genes result in pathological dysregulation of mitophagy, contributing to neurodegeneration. Here, we report that environmental factors causing a specific posttranslational modification on PINK1 can mimic these genetic mutations. We describe a molecular mechanism for impairment of mitophagy via formation of S-nitrosylated PINK1 (SNO-PINK1). Mitochondrial insults simulating age- or environmental-related stress lead to increased SNO-PINK1, inhibiting its kinase activity. SNO-PINK1 decreases Parkin translocation to mitochondrial membranes, disrupting mitophagy in cell lines and human-iPSC-derived neurons. We find levels of SNO-PINK1 in brains of α-synuclein transgenic PD mice similar to those in cell-based models, indicating the pathophysiological relevance of our findings. Importantly, SNO-PINK1-mediated deficits in mitophagy contribute to neuronal cell death. These results reveal a direct molecular link between nitrosative stress, SNO-PINK1 formation, and mitophagic dysfunction that contributes to the pathogenesis of PD.http://www.sciencedirect.com/science/article/pii/S2211124717315310PARK6PINK1PARK2ParkinParkinson’s diseasemitophagyS-nitrosylation |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Chang-Ki Oh Abdullah Sultan Joseph Platzer Nima Dolatabadi Frank Soldner Daniel B. McClatchy Jolene K. Diedrich John R. Yates, III Rajesh Ambasudhan Tomohiro Nakamura Rudolf Jaenisch Stuart A. Lipton |
spellingShingle |
Chang-Ki Oh Abdullah Sultan Joseph Platzer Nima Dolatabadi Frank Soldner Daniel B. McClatchy Jolene K. Diedrich John R. Yates, III Rajesh Ambasudhan Tomohiro Nakamura Rudolf Jaenisch Stuart A. Lipton S-Nitrosylation of PINK1 Attenuates PINK1/Parkin-Dependent Mitophagy in hiPSC-Based Parkinson’s Disease Models Cell Reports PARK6 PINK1 PARK2 Parkin Parkinson’s disease mitophagy S-nitrosylation |
author_facet |
Chang-Ki Oh Abdullah Sultan Joseph Platzer Nima Dolatabadi Frank Soldner Daniel B. McClatchy Jolene K. Diedrich John R. Yates, III Rajesh Ambasudhan Tomohiro Nakamura Rudolf Jaenisch Stuart A. Lipton |
author_sort |
Chang-Ki Oh |
title |
S-Nitrosylation of PINK1 Attenuates PINK1/Parkin-Dependent Mitophagy in hiPSC-Based Parkinson’s Disease Models |
title_short |
S-Nitrosylation of PINK1 Attenuates PINK1/Parkin-Dependent Mitophagy in hiPSC-Based Parkinson’s Disease Models |
title_full |
S-Nitrosylation of PINK1 Attenuates PINK1/Parkin-Dependent Mitophagy in hiPSC-Based Parkinson’s Disease Models |
title_fullStr |
S-Nitrosylation of PINK1 Attenuates PINK1/Parkin-Dependent Mitophagy in hiPSC-Based Parkinson’s Disease Models |
title_full_unstemmed |
S-Nitrosylation of PINK1 Attenuates PINK1/Parkin-Dependent Mitophagy in hiPSC-Based Parkinson’s Disease Models |
title_sort |
s-nitrosylation of pink1 attenuates pink1/parkin-dependent mitophagy in hipsc-based parkinson’s disease models |
publisher |
Elsevier |
series |
Cell Reports |
issn |
2211-1247 |
publishDate |
2017-11-01 |
description |
Mutations in PARK6 (PINK1) and PARK2 (Parkin) are linked to rare familial cases of Parkinson’s disease (PD). Mutations in these genes result in pathological dysregulation of mitophagy, contributing to neurodegeneration. Here, we report that environmental factors causing a specific posttranslational modification on PINK1 can mimic these genetic mutations. We describe a molecular mechanism for impairment of mitophagy via formation of S-nitrosylated PINK1 (SNO-PINK1). Mitochondrial insults simulating age- or environmental-related stress lead to increased SNO-PINK1, inhibiting its kinase activity. SNO-PINK1 decreases Parkin translocation to mitochondrial membranes, disrupting mitophagy in cell lines and human-iPSC-derived neurons. We find levels of SNO-PINK1 in brains of α-synuclein transgenic PD mice similar to those in cell-based models, indicating the pathophysiological relevance of our findings. Importantly, SNO-PINK1-mediated deficits in mitophagy contribute to neuronal cell death. These results reveal a direct molecular link between nitrosative stress, SNO-PINK1 formation, and mitophagic dysfunction that contributes to the pathogenesis of PD. |
topic |
PARK6 PINK1 PARK2 Parkin Parkinson’s disease mitophagy S-nitrosylation |
url |
http://www.sciencedirect.com/science/article/pii/S2211124717315310 |
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