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PreprintCited by 39Parkinson's Disease Mechanisms and TreatmentsMitochondrial Function and PathologyAutophagy in Disease and Therapy

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Mechanism of human PINK1 activation at the TOM complex in a reconstituted system

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Raimi, Olawale G., Ojha, Hina, Ehses, Kenneth, Dederer, Verena, Lange, Sven M, Rivera, Cristian Polo, Deegan, Tom D., Chen, Yinchen, Wightman, Melanie, Toth, Rachel, Labib, Karim P. M., Mathea, Sebastian, Ranson, Neil, Fernández-Busnadiego, Rubén, Muqit, Miratul M. K.·2023·Science Advances
DOI 10.1101/2023.12.23.573181PMC PMC11160474

Preprint — published as 10.1126/sciadv.adn7191

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Abstract

Loss of function mutations in PTEN-induced kinase 1 (PINK1) are a frequent cause of early-onset Parkinson’s disease (PD). Stabilisation of PINK1 at the Translocase of Outer Membrane (TOM) complex of damaged mitochondria is a critical step for its activation. To date the mechanism of how PINK1 is activated in the TOM complex is unclear. Herein we report co-expression of human PINK1 and all seven TOM subunits in Saccharomyces cerevisiae is sufficient for PINK1 activation. We use this reconstitution system to systematically assess the role of each TOM subunit towards PINK1 activation. We unambiguously demonstrate that the TOM20 and TOM70 receptor subunits are required for optimal PINK1 activation and map their sites of interaction with PINK1 using AlphaFold structural modelling and mutagenesis. We also demonstrate an essential role of the pore-containing subunit TOM40 and its structurally associated subunits TOM7 and TOM22 for PINK1 activation. These molecular findings will aid in the development of small molecule activators of PINK1 as a therapeutic strategy for PD.

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Metadata

Authors
Raimi, O. G., Ojha, H., Ehses, K., Dederer, V., Lange, S. M., Rivera, C. P., Deegan, T. D., Chen, Y., Wightman, M., Toth, R., Labib, K. P. M., Mathea, S., Ranson, N., Fernández-Busnadiego, R., & Muqit, M. M. K.
Affiliations
  • University of Dundee (GB)
  • Universitätsmedizin Göttingen (DE)
  • Goethe University Frankfurt (DE)
  • University of Leeds (GB)
Corresponding author
Muqit, Miratul M. K.
ORCID
Venue
Science Advances
Publisher
openRxiv
Published
2023-12-23
Volume
10
Issue
23
Pages
eadn7191-eadn7191
ISSN
2375-2548 (ISSN-L)
DOI
10.1101/2023.12.23.573181
PMC
PMC11160474
OpenAlex
W4399425564
Cited by
39
References
1
Citations by year
2026: 15 · 2025: 21 · 2024: 3
FWCI
10.43
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Science Advances (publishedVersion, cc-by-nc)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Discovery Research Portal (University of Dundee) (publishedVersion, cc-by-nc)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
  • Discovery Research Portal (University of Dundee) (submittedVersion, cc-by)
  • GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, other-oa)
  • GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by)
Funders
  • Michael J. Fox Foundation for Parkinson's Research (ASAP-000282, ASAP‐000463)
  • University of Dundee
  • Wellcome Trust (210753/Z/18/Z)
  • Cancer Research UK (24558, C578/A24558, DRCRPG-Nov22/100016, C578/A25669)
  • Deutsche Forschungsgemeinschaft (EXC 2067, 390729940, EXC 2067/1390729940)
  • Medical Research Council (MC_UU_00035/4)
Topics
  • Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
Keywords
PINK1, TOM complex, Parkinson's disease, Tom20, Tom70, Tom40, Tom22, mitochondrial translocase, protein-protein interaction, reconstituted system, Saccharomyces cerevisiae, small molecule activators
MeSH terms
Mitochondrial Precursor Protein Import Complex Proteins, PTEN-Induced Putative Kinase, Enzyme Activation, Humans, Mitochondria, Models, Molecular, Protein Binding, Protein Kinases, Saccharomyces cerevisiae, Protein Subunits, Saccharomyces cerevisiae Proteins, Mitochondrial Membrane Transport Proteins

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