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High-content genome-wide RNAi screens identify regulators of parkin upstream of mitophagy
Open accessAbstract
An increasing body of evidence points to mitochondrial dysfunction as a contributor to the molecular pathogenesis of neurodegenerative diseases such as Parkinson's disease. Recent studies of the Parkinson's disease associated genes PINK1 (ref. 2) and parkin (PARK2, ref. 3) indicate that they may act in a quality control pathway preventing the accumulation of dysfunctional mitochondria. Here we elucidate regulators that have an impact on parkin translocation to damaged mitochondria with genome-wide small interfering RNA (siRNA) screens coupled to high-content microscopy. Screening yielded gene candidates involved in diverse cellular processes that were subsequently validated in low-throughput assays. This led to characterization of TOMM7 as essential for stabilizing PINK1 on the outer mitochondrial membrane following mitochondrial damage. We also discovered that HSPA1L (HSP70 family member) and BAG4 have mutually opposing roles in the regulation of parkin translocation. The screens revealed that SIAH3, found to localize to mitochondria, inhibits PINK1 accumulation after mitochondrial insult, reducing parkin translocation. Overall, our screens provide a rich resource to understand mitochondrial quality control.
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“Multiple genome-wide siRNA/CRISPR-Cas9 screens have already identified mitophagy genes although with little overlap between studies [15–18].”
From miRNA family miR-29 inhibits PINK1-PRKN signaling via ATG9A (2026) · cites this paper as [16]
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Cites
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Metadata
- Authors
- Hasson, S. A., Kane, L. A., Yamano, K., Huang, C.-H., Sliter, D. A., Buehler, E., Wang, C., Heman-Ackah, S. M., Hessa, T., Guha, R., Martin, S. E., & Youle, R. J.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Youle, Richard J.
- ORCID
- Venue
- Nature
- Published
- 2013-11-24
- Volume
- 504
- Issue
- 7479
- Pages
- 291-295
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5841086
- OpenAlex
- W2091264505
- Cited by
- 365
- References
- 30
- Citations by year
- 2026: 15 · 2025: 19 · 2024: 25 · 2023: 16 · 2022: 27 · 2021: 36 · 2020: 32 · 2019: 38 · 2018: 27 · 2017: 27 · 2016: 31 · 2015: 36 · 2014: 36
- FWCI
- 21.81
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, public-domain)
- Funders
- National Institutes of Health (Z99 NS999999)
- National Institute of General Medical Sciences
- National Institute of Neurological Disorders and Stroke
- Topics
- Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- mitophagy, Parkin, PINK1, mitochondrial quality control, HSPA1L, mitochondrial outer membrane, Parkinson's disease, mitochondrial dysfunction, autophagy, ubiquitin ligase
- MeSH terms
- Mitochondrial Precursor Protein Import Complex Proteins, PTEN-Induced Putative Kinase, Multigene Family, HeLa Cells, Humans, Membrane Proteins, Mitochondria, Parkinson Disease, Protein Kinases, Reproducibility of Results, Genome, Human, HSP70 Heat-Shock Proteins, Protein Transport, Mitochondrial Proteins, RNA Interference, RNA, Small Interfering, Ubiquitin-Protein Ligases, HCT116 Cells, Adaptor Proteins, Signal Transducing, Mitochondrial Membranes, HEK293 Cells, Mitophagy
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