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Cited by 29Parkinson's Disease Mechanisms and TreatmentsAutophagy in Disease and TherapyUbiquitin and proteasome pathways

Substitution of PINK1 Gly411 modulates substrate receptivity and turnover

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Fiesel, Fabienne C, Fričová, Dominika, Hayes, Caleb S, Coban, Mathew A, Hudec, Roman, Bredenberg, Jenny M, Broadway, Benjamin J, Markham, Briana N +17 more·2023·Autophagy
DOI 10.1080/15548627.2022.2151294PMC PMC10262784
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Abstract

The ubiquitin (Ub) kinase-ligase pair PINK1-PRKN mediates the degradation of damaged mitochondria by macroautophagy/autophagy (mitophagy). PINK1 surveils mitochondria and upon stress accumulates on the mitochondrial surface where it phosphorylates serine 65 of Ub to activate PRKN and to drive mitochondrial turnover. While loss of either PINK1 or PRKN is genetically linked to Parkinson disease (PD) and activating the pathway seems to have great therapeutic potential, there is no formal proof that stimulation of mitophagy is always beneficial. Here we used biochemical and cell biological methods to study single nucleotide variants in the activation loop of PINK1 to modulate the enzymatic function of this kinase. Structural modeling and in vitro kinase assays were used to investigate the molecular mechanism of the PINK1 variants. In contrast to the PD-linked PINK1G411S mutation that diminishes Ub kinase activity, we found that the PINK1G411A variant significantly boosted Ub phosphorylation beyond levels of PINK1 wild type. This resulted in augmented PRKN activation, mitophagy rates and increased viability after mitochondrial stress in midbrain-derived, gene-edited neurons. Mechanistically, the G411A variant stabilizes the kinase fold of PINK1 and transforms Ub to adopt the preferred, C-terminally retracted conformation for improved substrate turnover. In summary, we identify a critical role of residue 411 for substrate receptivity that may now be exploited for drug discovery to increase the enzymatic function of PINK1. The genetic substitution of Gly411 to Ala increases mitophagy and may be useful to confirm neuroprotection in vivo and might serve as a critical positive control during therapeutic development.Abbreviations: ATP: adenosine triphosphate; CCCP: carbonyl cyanide m-chlorophenyl hydrazone; Ub-CR: ubiquitin with C-terminally retracted tail; CTD: C-terminal domain (of PINK1); ELISA: enzyme-linked immunosorbent assay; HCI: high-content imaging; IB: immunoblot; IF: immunofluorescence; NPC: neuronal precursor cells; MDS: molecular dynamics simulation; PD: Parkinson disease; p-S65-Ub: ubiquitin phosphorylated at Ser65; RMSF: root mean scare fluctuation; TOMM: translocase of outer mitochondrial membrane; TVLN: ubiquitin with T66V and L67N mutation, mimics Ub-CR; Ub: ubiquitin; WT: wild-type.

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  • The machine-learning classifier had excellent agreement with the established GFP-PRKN ratio algorithm and a combined Z' score of 0.79.

    “There was excellent agreement between the new classifier and the established ‘GFP-PRKN ratio’ algorithm [19, 20, 25, 30] (Fig. 1C, Table S4) but the new classifier was more robust in this screening setting and had a combined Z’ score of 0.79.”

    From miRNA family miR-29 inhibits PINK1-PRKN signaling via ATG9A (2026) · cites this paper as [30]

    The Results section (‘PINK1G411A is a more active Ub kinase’; page unavailable) reports high-content quantification of GFP-PRKN translocation, and the high-content imaging Methods describe those measurements. Our copy does not identify a ‘GFP-PRKN ratio’ algorithm or report agreement with a machine-learning classifier or a combined Z′ score of 0.79. (LLM, conf=0.78)

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Authors
Fiesel, F. C., Fričová, D., Hayes, C. S., Coban, M. A., Hudec, R., Bredenberg, J. M., Broadway, B. J., Markham, B. N., Yan, T., Boneski, P. K., Fiorino, G., Watzlawik, J. O., Hou, X., McCarty, A. M., Lewis-Tuffin, L. J., Zhong, J., Madden, B. J., Ordureau, A., An, H., Puschmann, A., Wszolek, Z. K., Ross, O. A., Harper, J. W., Caulfield, T. R., & Springer, W.
Affiliations
  • Mayo Clinic (US)
  • Mayo Clinic
  • Cytometry and Imaging Laboratory, Department of Research, Mayo Clinic, Jacksonville, FL, USA
  • Harvard University (US)
  • Lund University (SE)
Corresponding author
Springer, Wolfdieter
ORCID
Venue
Autophagy
Publisher
Informa UK Limited
Published
2022-12-05
Volume
19
Issue
6
Pages
1711-1732
ISSN
  • 1554-8627 (ISSN-L)
  • 1554-8635
DOI
10.1080/15548627.2022.2151294
PMC
PMC10262784
OpenAlex
W4310775732
Cited by
29
References
81
Citations by year
2026: 7 · 2025: 5 · 2024: 10 · 2023: 7
FWCI
2.90
Type
journal article
Language
en
Open access
Licence
Locations
  • Autophagy (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Figshare (submittedVersion, cc-by)
  • Lund University Publications (Lund University) (submittedVersion)
  • Figshare (cc-by)
Funders
  • National Institute on Aging (AG062556)
  • NINDS (NS085070)
  • Department of Defense Congressionally Directed Medical Research Programs (W81XWH-17-1-0248)
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Keywords
Parkin, mitophagy, Parkinson's disease, ubiquitin phosphorylation, mitochondrial stress, neuroprotection, single nucleotide variants
MeSH terms
Autophagy, Humans, Parkinson Disease, Protein Kinases, Ubiquitin, Ubiquitin-Protein Ligases

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