S-Nitrosylation of PINK1 Attenuates PINK1/Parkin-Dependent Mitophagy in hiPSC-Based Parkinson's Disease Models

Chang Ki Oh, Abdullah Sultan, Joseph Platzer, Nima Dolatabadi, Frank Soldner, Daniel B. McClatchy, Jolene K. Diedrich, John R. Yates, Rajesh Ambasudhan, Tomohiro Nakamura, Rudolf Jaenisch, Stuart A. Lipton

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31 Scopus citations

Abstract

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. Nitrosative stress and mitochondrial dysfunction represent key pathological events in Parkinson's disease. Oh et al. identify a molecular link between these events in which increased nitric oxide (NO)-related species S-nitrosylate a critical thiol group in PINK1, thus compromising its ability to eliminate damaged mitochondria via mitophagy.

Original languageEnglish (US)
Pages (from-to)2171-2182
Number of pages12
JournalCell Reports
Volume21
Issue number8
DOIs
StatePublished - Nov 21 2017

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Keywords

  • PARK2
  • PARK6
  • PINK1
  • Parkin
  • Parkinson's disease
  • S-nitrosylation
  • mitophagy

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Oh, C. K., Sultan, A., Platzer, J., Dolatabadi, N., Soldner, F., McClatchy, D. B., Diedrich, J. K., Yates, J. R., Ambasudhan, R., Nakamura, T., Jaenisch, R., & Lipton, S. A. (2017). S-Nitrosylation of PINK1 Attenuates PINK1/Parkin-Dependent Mitophagy in hiPSC-Based Parkinson's Disease Models. Cell Reports, 21(8), 2171-2182. https://doi.org/10.1016/j.celrep.2017.10.068