MicroRNA-593-5p contributes to cell death following exposure to 1-methyl-4-phenylpyridinium by targeting PTEN-induced putative kinase 1
Open accessAbstract
Neurodegenerative diseases are characterized by a decline in neuronal function and structure, leading to neuronal death. Understanding the molecular mechanisms of neuronal death is crucial for developing therapeutics. MiRs are small noncoding RNAs that regulate gene expression by degrading target mRNAs or inhibiting translation. MiR dysregulation has been linked to many neurodegenerative diseases, but the underlying mechanisms are not well understood. As mitochondrial dysfunction is one of the common molecular mechanisms leading to neuronal death in many neurodegenerative diseases, here we studied miRs that modulate neuronal death caused by 1-methyl-4-phenylpyridinium (MPP + ), an inhibitor of complex I in mitochondria. We identified miR-593-5p, levels of which were increased in SH-SY5Y human neuronal cells, after exposure to MPP + . We found that intracellular Ca 2+ , but not of reactive oxygen species, mediated this miR-593-5p increase. Furthermore, we found the increase in miR-593-5p was due to enhanced stability, not increased transcription or miR processing. Importantly, we show the increase in miR-593-5p contributed to MPP + -induced cell death. Our data revealed that miR-593-5p inhibits a signaling pathway involving PTEN-induced putative kinase 1 (PINK1) and Parkin, two proteins responsible for the removal of damaged mitochondria from cells, by targeting the coding sequence of PINK1 mRNA. Our findings suggest that miR-593-5p contributes to neuronal death resulting from MPP + toxicity, in part, by impeding the PINK1/Parkin-mediated pathway that facilitates the clearance of damaged mitochondria. Taken together, our observations highlight the potential significance of inhibiting miR-593-5p as a therapeutic approach for neurodegenerative diseases.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Of the five miRNAs experimentally confirmed to directly target PINK1, only miR-27b was among the top hits in the genome-wide screen.
“However, of the five miRNAs that have been experimentally confirmed to directly target PINK1 [37–39], only miR-27b [32] was among the top hits in our genome-wide screen.”
From miRNA family miR-29 inhibits PINK1-PRKN signaling via ATG9A (2026) · cites this paper as [39]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
1 retracted
RETRACTED: Efficient Derivation of Functional Floor Plate Tissue from Human Embryonic Stem Cells
Fasano, C. A., Chambers, S. M., Lee, G., Tomishima, M. J., & Studer, L. (2010) · Cell stem cell · doi:10.1016/j.stem.2010.03.001 · Cited by 210 · see citing works
RetractedMicroRNAs: small RNAs with a big role in gene regulation
He, L., & Hannon, G. J. (2004) · Nature Reviews Genetics · doi:10.1038/nrg1379 · Cited by 5,910 · see citing works
MicroRNA therapeutics: towards a new era for the management of cancer and other diseases
Rupaimoole, R., & Slack, F. J. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.246 · Cited by 4,741 · cited 6× · see citing works
“(2023) 299(5) 104709 inducers, such as etoposide (DNA damage) or staurosporine (nonselective protein kinase inhibitor) (Fig.”
BackgroundMethodInfluentialmiRBase: from microRNA sequences to function
Kozomara, A., Birgaoanu, M., & Griffiths-Jones, S. (2019) · Nucleic Acids Research · doi:10.1093/nar/gky1141 · Cited by 4,684 · see citing works
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 · see citing works
Chronic systemic pesticide exposure reproduces features of Parkinson's disease
Betarbet, R., Sherer, T., Mackenzie, G., Garcia-Osuna, M., Panov, A., & Greenamyre, J. (2000) · Nature Neuroscience · doi:10.1038/81834 · Cited by 3,797 · see citing works
Bartel, D. P. (2018) · Cell · doi:10.1016/j.cell.2018.03.006 · Cited by 3,751 · see citing works
Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling
Chambers, S. M., Fasano, C. A., Papapetrou, E. P., Tomishima, M., Sadelain, M., & Studer, L. (2009) · Nature Biotechnology · doi:10.1038/nbt.1529 · Cited by 3,620 · see citing works
Youle, R. J., & Narendra, D. P. (2011) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3028 · Cited by 3,273 · see citing works
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 · see citing works
Transcriptome-wide Identification of RNA-Binding Protein and MicroRNA Target Sites by PAR-CLIP
Hafner, M., Landthaler, M., Burger, L., Khorshid, M., Hausser, J., Berninger, P., Rothballer, A., Ascano, M., Jungkamp, A.-C., Munschauer, M., et al. (2010) · Cell · doi:10.1016/j.cell.2010.03.009 · Cited by 2,873 · see citing works
Mitochondrial Complex I Deficiency in Parkinson's Disease
Schapira, A. H. V., Cooper, J. M., Dexter, D., Clark, J. B., Jenner, P., & Marsden, C. D. (1990) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1990.tb02325.x · Cited by 2,283 · see citing works
Regulation of microRNA function in animals
Gebert, L. F. R., & MacRae, I. J. (2019) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-018-0045-7 · Cited by 2,031 · see citing works
Matsuda, N., Sato, S., Shiba, K., Okatsu, K., Saisho, K., Gautier, C. A., Sou, Y.-S., Saiki, S., Kawajiri, S., Sato, F., et al. (2010) · Journal of Cell Biology · doi:10.1083/jcb.200910140 · Cited by 1,969 · see citing works
Argonaute HITS-CLIP decodes microRNA–mRNA interaction maps
Chi, S. W., Zang, J. B., Mele, A., & Darnell, R. B. (2009) · Nature · doi:10.1038/nature08170 · Cited by 1,791 · see citing works
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 · see citing works
Langston, J. W., Forno, L. S., Rebert, C. S., & Irwin, I. (1984) · Brain Research · doi:10.1016/0006-8993(84)90777-7 · Cited by 922 · see citing works
Parkin is activated by PINK1-dependent phosphorylation of ubiquitin at Ser65
Kazlauskaite, A., Kondapalli, C., Gourlay, R., Campbell, D. G., Ritorto, M. S., Hofmann, K., Alessi, D. R., Knebel, A., Trost, M., & Muqit, M. M. K. (2014) · Biochemical Journal · doi:10.1042/bj20140334 · Cited by 806 · see citing works
Mattson, M. P. (2007) · Aging Cell · doi:10.1111/j.1474-9726.2007.00275.x · Cited by 751 · see citing works
Repression of α-synuclein expression and toxicity by microRNA-7
Junn, E., Lee, K.-W., Jeong, B. S., Chan, T. W., Im, J.-Y., & Mouradian, M. M. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0906277106 · Cited by 634 · see citing works
Self-citationTarget RNA–Directed Trimming and Tailing of Small Silencing RNAs
Ameres, S. L., Horwich, M. D., Hung, J.-H., Xu, J., Ghildiyal, M., Weng, Z., & Zamore, P. D. (2010) · Science · doi:10.1126/science.1187058 · Cited by 597 · see citing works
Down-Regulation of a Host MicroRNA by a <i>Herpesvirus saimiri</i> Noncoding RNA
Cazalla, D., Yario, T., & Steitz, J. A. (2010) · Science · doi:10.1126/science.1187197 · Cited by 474 · see citing works
Mitochondrial dysfunction and oxidative stress in Parkinson's disease and monogenic parkinsonism
Hauser, D. N., & Hastings, T. G. (2012) · Neurobiology of Disease · doi:10.1016/j.nbd.2012.10.011 · Cited by 470 · see citing works
Calcium signaling and neurodegenerative diseases
Борисович, Б. И. (2009) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2009.01.001 · Cited by 467 · see citing works
Differentiation of the SH-SY5Y Human Neuroblastoma Cell Line
Shipley, M. M., Mangold, C. A., & SZPARA, M. L. (2016) · Journal of Visualized Experiments · doi:10.3791/53193 · Cited by 449 · see citing works
Haas, R. H., Nasirian, F., Nakano, K., Ward, D., Pay, M., Hill, R., & Shults, C. W. (1995) · Annals of Neurology · doi:10.1002/ana.410370604 · Cited by 435 · see citing works
Analysis of CDS-located miRNA target sites suggests that they can effectively inhibit translationPreprint
Hausser, J., Syed, A. P., Bilen, B., & Zavolan, M. (2013) · Genome Research · doi:10.1101/gr.139758.112 · Cited by 336 · see citing works
Hasegawa, E., Takeshige, K., Oishi, T., Murai, Y., & Minakami, S. (1990) · Biochemical and Biophysical Research Communications · doi:10.1016/0006-291x(90)90498-c · Cited by 320 · see citing works
The kinase domain of mitochondrial PINK1 faces the cytoplasm
Zhou, C. H., Huang, Y., Shao, Y., May, J., Prou, D., Perier, C., Dauer, W. T., Schon, E. A., & Przedborski, S. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0802814105 · Cited by 312 · see citing works
The PINK1/Parkin-mediated mitophagy is compromised by PD-associated mutations
Geisler, S., Holmström, K. M., Treis, A., Skujat, D., Weber, S. S., Fiesel, F. C., Kahle, P. J., & Springer, W. (2010) · Autophagy · doi:10.4161/auto.6.7.13286 · Cited by 311 · see citing works
Donato, R., Miljan, E., Hines, S. J., Aouabdi, S., Pollock, K., Patel, S., Edwards, F. A., & Sinden, J. D. (2007) · BMC Neuroscience · doi:10.1186/1471-2202-8-36 · Cited by 308 · see citing works
Structural Basis for Target-Directed MicroRNA Degradation
Sheu-Gruttadauria, J., Pawlica, P., Klum, S. M., Wang, S., Yario, T. A., Schirle Oakdale, N. T., Steitz, J. A., & MacRae, I. J. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.06.019 · Cited by 246 · see citing works
Kinetic Analysis Reveals the Fate of a MicroRNA following Target Regulation in Mammalian Cells
Baccarini, A., Chauhan, H., Gardner, T. J., Jayaprakash, A. D., Sachidanandam, R., & Brown, B. D. (2011) · Current Biology · doi:10.1016/j.cub.2011.01.067 · Cited by 235 · see citing works
MicroRNAs in neurodegenerative diseases and their therapeutic potential
Junn, E., & Mouradian, M. M. (2011) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2011.10.002 · Cited by 222 · see citing works
Self-citationTranscriptome-wide Discovery of microRNA Binding Sites in Human Brain
Boudreau, R. L., Jiang, P., Gilmore, B. L., Spengler, R. M., Tirabassi, R., Nelson, J. A., Ross, C. A., Xing, Y., & Davidson, B. L. (2014) · Neuron · doi:10.1016/j.neuron.2013.10.062 · Cited by 217 · see citing works
The influence of dose and dosing interval on MPTP-induced dopaminergic neurotoxicity in mice
Sonsalla, P. K., & Heikkila, R. E. (1986) · European Journal of Pharmacology · doi:10.1016/0014-2999(86)90444-9 · Cited by 211 · see citing works
Mitochondrial complex I and II activities of lymphocytes and platelets in Parkinson's disease
Yoshino, H., Nakagawa-Hattori, Y., Kondo, T., & Mizuno, Y. (1992) · Journal of Neural Transmission - Parkinsons Disease and Dementia Section · doi:10.1007/bf02257619 · Cited by 195 · see citing works
Tracking Distinct RNA Populations Using Efficient and Reversible Covalent Chemistry
Duffy, E. E., Rutenberg-Schoenberg, M., Stark, C., Kitchen, R. R., Gerstein, M., & Simon, M. D. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.07.023 · Cited by 193 · see citing works
Brümmer, A., & Hausser, J. (2014) · BioEssays · doi:10.1002/bies.201300104 · Cited by 185 · see citing works
Degradation dynamics of microRNAs revealed by a novel pulse-chase approachPreprint
Marzi, M. J., Ghini, F., Cerruti, B., de Pretis, S., Bonetti, P., Giacomelli, C., Gorski, M. M., Kress, T. R., Pelizzola, M., Müller, H., et al. (2016) · Genome Research · doi:10.1101/gr.198788.115 · Cited by 184 · see citing works
Limitations of Animal Models of Parkinson's Disease
Potashkin, J. A., Blume, S. R., & Runkle, N. K. (2010) · Parkinson s Disease · doi:10.4061/2011/658083 · Cited by 180 · see citing works
A novel class of microRNA-recognition elements that function only within open reading frames
Zhang, K., Zhang, X., Cai, Z., Zhou, J., Cao, R., Zhao, Y., Chen, Z., Wang, D., Ruan, W., Zhao, Q. C., et al. (2018) · Nature Structural & Molecular Biology · doi:10.1038/s41594-018-0136-3 · Cited by 169 · see citing works
Choi, W., Lee, E. H., Chung, C.-W., Jung, Y., Jin, B. K., Kim, S. U., Oh, T. H., Saido, T. C., & Oh, Y. J. (2001) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2001.00368.x · Cited by 128 · see citing works
Tudor-SN–mediated endonucleolytic decay of human cell microRNAs promotes G 1 /S phase transition
Elbarbary, R. A., Miyoshi, K., Myers, J. R., Du, P., Ashton, J. M., Tian, B., & Maquat, L. E. (2017) · Science · doi:10.1126/science.aai9372 · Cited by 108 · see citing works
MicroRNA-7 Protects against 1-Methyl-4-Phenylpyridinium-Induced Cell Death by Targeting RelA
Choi, D. C., Chae, Y.-J., Kabaria, S., Chaudhuri, A. D., Jain, M. R., Li, H., Mouradian, M. M., & Junn, E. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.0985-14.2014 · Cited by 103 · see citing works
Self-citationCalcium, mitochondrial dysfunction and slowing the progression of Parkinson's disease
Surmeier, D. J., Halliday, G. M., & Simuni, T. (2017) · Experimental Neurology · doi:10.1016/j.expneurol.2017.08.001 · Cited by 99 · see citing works
Godnic, I., Zorc, M., Skok, D. J., Călin, G. A., Horvat, S., Dovč, P., Kovač, M., & Kunej, T. (2013) · PLoS ONE · doi:10.1371/journal.pone.0065165 · Cited by 84 · see citing works
Jung, S., Chung, Y., Lee, Y., Lee, Y., Cho, J. W., Shin, E., Kim, H., & Oh, Y. J. (2019) · Cell Death Discovery · doi:10.1038/s41420-019-0210-6 · Cited by 31 · see citing works
Verma, M., Zhu, J., Wang, K. Z. Q., & Chu, C. T. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra119.010474 · Cited by 29 · see citing works
MicroRNAs in neurodegenerative disorders
Junn, E., & Mouradian, M. M. (2010) · Cell Cycle · doi:10.4161/cc.9.9.11296 · Cited by 25 · see citing works
Self-citationKoufaris, C. (2016) · BioEssays · doi:10.1002/bies.201500135 · Cited by 20 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Mechanism and Therapeutic Prospect of miRNAs in Neurodegenerative Diseases
Ma, Y.-M., & Zhao, L. (2023) · Behavioural Neurology · doi:10.1155/2023/8537296 · Cited by 34 · see citing works
miRNA family miR-29 inhibits PINK1-PRKN dependent mitophagy via ATG9APreprint
Markham, B. N., Ramnarine, C., Kim, S., Grever, W. E., Soto‐Beasley, A. I., Heckman, M. G., Ren, Y., Osborne, A. C., Bhagwate, A. V., Liu, Y., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.01.17.576122 · Cited by 7 · see citing works
Qiao, Y., Kou, J., Tian, Y., Ma, W., Yu, Y., Pang, J., Pei, Y., Zhang, Y., Ye, B., Xie, Z., et al. (2024) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2024.107773 · Cited by 4 · see citing works
miRNA family miR-29 inhibits PINK1-PRKN signaling via ATG9A
Markham, B. N., Ramnarine, C., Kim, S., Grever, W. E., Soto-Beasley, A. I., Heckman, M. G., Ren, Y., Osborne, A. C., Kehili, M., Bhagwate, A. V., et al. (2026) · Molecular Neurodegeneration Advances · doi:10.1186/s44477-026-00029-w
Afrooghe, A., Ahmadi, E., Shayan, M., Ohadi, M. A. D., Behnoush, A. H., & Dehpour, A. R. (2025) · Journal of Pharmacy and Pharmacology · doi:10.1093/jpp/rgaf039
The Diagnostic and Therapeutic Value of Micro-RNA in Parkinson’s Disease
Lin, G.-L., Wang, Y., & Cheng, B.-H. (2026) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-026-01767-x
- Authors
- Yoo, M., Choi, D. C., Murphy, A., Ahsan, A. M., & Junn, E.
- Affiliations
- Rutgers, The State University of New Jersey (US)
- Corresponding author
- Junn, Eunsung
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2023-05
- Volume
- 299
- Issue
- 5
- Pages
- 104709
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC10196868
- OpenAlex
- W4365517465
- Cited by
- 6
- References
- 51
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 2 · 2023: 1
- FWCI
- 0.76
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (NS70898, NS095003)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- microRNA, MPP+, PINK1, Parkin, neuronal cell death, mitochondrial dysfunction, mitochondrial complex I inhibition, intracellular calcium, miRNA stability, neurodegenerative diseases, SH-SY5Y cells, autophagy
- MeSH terms
- PTEN-Induced Putative Kinase, Humans, Neuroblastoma, Protein Kinases, 1-Methyl-4-phenylpyridinium, Cell Death, Apoptosis, MicroRNAs, Ubiquitin-Protein Ligases, Cell Line, Tumor
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
