The DOI matches its Crossref record; 30 of the 30 references it cites were found in a registry or an index.
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
Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism
Kitada, T., Asakawa, S., Hattori, N., Matsumine, H., Yamamura, Y., Minoshima, S., Yokochi, M., Mizuno, Y., & Shimizu, N. (1998) · Nature · doi:10.1038/33416 · Cited by 5,227
Parkin is recruited selectively to impaired mitochondria and promotes their autophagy
Narendra, D., Tanaka, A., Suen, D.-F., & Youle, R. J. (2008) · The Journal of Cell Biology · doi:10.1083/jcb.200809125 · Cited by 4,026
Self-citationHereditary Early-Onset Parkinson's Disease Caused by Mutations in PINK1
Valente, E. M., Abou-Sleiman, P. M., Caputo, V., Muqit, M. M. K., Harvey, K., Gispert, S., Ali, Z., Del Turco, D., Bentivoglio, A. R., Healy, D. G., et al. (2004) · Science · doi:10.1126/science.1096284 · Cited by 3,481
PINK1 Is Selectively Stabilized on Impaired Mitochondria to Activate Parkin
Narendra, D. P., Jin, S. M., Tanaka, A., Suen, D.-F., Gautier, C. A., Shen, J., Cookson, M. R., & Youle, R. J. (2010) · PLoS Biology · doi:10.1371/journal.pbio.1000298 · Cited by 2,944
Self-citationPINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1
Geisler, S., Holmström, K. M., Skujat, D., Fiesel, F. C., Rothfuss, O. C., Kahle, P. J., & Springer, W. (2010) · Nature Cell Biology · doi:10.1038/ncb2012 · Cited by 2,835
PINK1-dependent recruitment of Parkin to mitochondria in mitophagy
Vives-Bauza, C., Zhou, C., Huang, Y., Cui, M., de Vries, R. L. A., Kim, J., May, J., Tocilescu, M. A., Liu, W., Ko, H. S., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0911187107 · Cited by 1,616
Mitochondrial membrane potential regulates PINK1 import and proteolytic destabilization by PARL
Jin, S. M., Lazarou, M., Wang, C., Kane, L. A., Narendra, D. P., & Youle, R. J. (2010) · Journal of Cell Biology · doi:10.1083/jcb.201008084 · Cited by 1,375
Self-citationLandscape of the PARKIN-dependent ubiquitylome in response to mitochondrial depolarization
Sarraf, S. A., Raman, M., Guarani-Pereira, V., Sowa, M. E., Huttlin, E. L., Gygi, S. P., & Harper, J. W. (2013) · Nature · doi:10.1038/nature12043 · Cited by 1,010
Broad activation of the ubiquitin–proteasome system by Parkin is critical for mitophagy
Chan, N. C., Salazar, A. M., Pham, A. H., Sweredoski, M. J., Kolawa, N. J., Graham, R. L. J., Hess, S., & Chan, D. C. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr048 · Cited by 993
Widespread siRNA “off-target” transcript silencing mediated by seed region sequence complementarity
Jackson, A. L., Burchard, J., Schelter, J. M., Chau, B. N., Cleary, M. A., Lim, L. P., & Linsley, P. S. (2006) · RNA · doi:10.1261/rna.25706 · Cited by 979
Cited by
Sorted by citations
The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy
Lazarou, M., Sliter, D. A., Kane, L. A., Sarraf, S. A., Wang, C., Burman, J. L., Sideris, D. P., Fogel, A. I., & Youle, R. J. (2015) · Nature · doi:10.1038/nature14893 · Cited by 2,774
Self-citationThe Roles of PINK1, Parkin, and Mitochondrial Fidelity in Parkinson’s Disease
Pickrell, A. M., & Youle, R. J. (2015) · Neuron · doi:10.1016/j.neuron.2014.12.007 · Cited by 2,310
Self-citationMitophagy and Quality Control Mechanisms in Mitochondrial Maintenance
Pickles, S., Vigié, P., & Youle, R. J. (2018) · Current Biology · doi:10.1016/j.cub.2018.01.004 · Cited by 2,081
Self-citationMechanisms of mitophagy in cellular homeostasis, physiology and pathology
Palikaras, K., Lionaki, E., & Tavernarakis, N. (2018) · Nature Cell Biology · doi:10.1038/s41556-018-0176-2 · Cited by 1,556
PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase activity
Kane, L. A., Lazarou, M., Fogel, A. I., Li, Y., Yamano, K., Sarraf, S. A., Banerjee, S., & Youle, R. J. (2014) · Journal of Cell Biology · doi:10.1083/jcb.201402104 · Cited by 1,298
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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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