Cited by 100Mitochondrial Function and PathologySignaling Pathways in DiseaseMultiple Sclerosis Research Studies

Selective Inhibition of the Mitochondrial Permeability Transition Pore Protects against Neurodegeneration in Experimental Multiple Sclerosis

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Warne, Justin, Pryce, Gareth, Hill, Julia M., Shi, Xiao, Lennerås, Felicia, Puentes, Fabiola, Kip, Maarten, Hilditch, Laura +9 more·2016·Journal of Biological Chemistry

Abstract

The mitochondrial permeability transition pore is a recognized drug target for neurodegenerative conditions such as multiple sclerosis and for ischemia-reperfusion injury in the brain and heart. The peptidylprolyl isomerase, cyclophilin D (CypD, PPIF), is a positive regulator of the pore, and genetic down-regulation or knock-out improves outcomes in disease models. Current inhibitors of peptidylprolyl isomerases show no selectivity between the tightly conserved cyclophilin paralogs and exhibit significant off-target effects, immunosuppression, and toxicity. We therefore designed and synthesized a new mitochondrially targeted CypD inhibitor, JW47, using a quinolinium cation tethered to cyclosporine. X-ray analysis was used to validate the design concept, and biological evaluation revealed selective cellular inhibition of CypD and the permeability transition pore with reduced cellular toxicity compared with cyclosporine. In an experimental autoimmune encephalomyelitis disease model of neurodegeneration in multiple sclerosis, JW47 demonstrated significant protection of axons and improved motor assessments with minimal immunosuppression. These findings suggest that selective CypD inhibition may represent a viable therapeutic strategy for MS and identify quinolinium as a mitochondrial targeting group for in vivo use.

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Crossref · 10.1074/jbc.m115.700385

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  • Pharmacological inhibitors of CYPD including CsA, SfA, and JW47 limit MPT-driven necrosis and confer protection in multiple rodent models of disease in which oxidative stress and cytosolic Ca2+ overload constitute major etiological determinants (e.g., neuronal, cardiac, renal ischemia/reperfusion).

    “Accordingly, pharmacological inhibitors of CYPD including cyclosporin A (CsA) [376 379–381], sanglifehrin A (SfA) [382, 383], and JW47 [384] limit MPT-driven necrosis and confer protection in multiple rodent models of disease in which oxidative stress and cytosolic Ca2+ overload constitute major etiological determinants (e.g., neuronal, cardiac, and renal ischemia/reperfusion).”

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Authors
Warne, J., Pryce, G., Hill, J. M., Shi, X., Lennerås, F., Puentes, F., Kip, M., Hilditch, L., Walker, P., Simone, M. I., Chan, A. W. E., Towers, G. J., Coker, A. R., Duchen, M. R., Szabadkai, G., Baker, D., & Selwood, D. L.
Affiliations
  • University College London (GB)
  • University of London (GB)
  • Queen Mary University of London (GB)
Corresponding author
  • Baker, David
  • Selwood, David L.
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2016-02
Volume
291
Issue
9
Pages
4356-4373
ISSN
0021-9258 (ISSN-L)
OpenAlex
W2205409324
Cited by
99
References
107
Citations by year
2026: 7 · 2025: 9 · 2024: 12 · 2023: 8 · 2022: 11 · 2021: 7 · 2020: 10 · 2019: 8 · 2018: 11 · 2017: 8 · 2016: 7 · 2013: 1
FWCI
3.77
Type
journal article
Language
en
Open access
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Padua Research Archive (University of Padova) (submittedVersion, cc-by)
  • UCL Discovery (University College London) (submittedVersion)
  • Figshare (submittedVersion, cc-by)
  • Queen Mary Research Online (Queen Mary University of London) (submittedVersion)
  • NOVA (University of Newcastle Australia) (submittedVersion)
Funders
  • Wellcome Trust (090940)
  • National Multiple Sclerosis Society
  • Eisai UK
  • Diamond Light Source (mx8922)
  • European Research Council
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
Keywords
mitochondrial permeability transition pore, cyclophilin D, multiple sclerosis, neurodegeneration, quinolinium cations, experimental autoimmune encephalomyelitis, axon protection, mitochondrial targeting, immunosuppression
MeSH terms
Peptidyl-Prolyl Isomerase F, Mitochondrial Permeability Transition Pore, Animals, Cells, Cultured, Cerebral Cortex, Cyclosporins, Humans, Liver, Male, Mice, Inbred Strains, Multiple Sclerosis, Mutation, Neurons, Peptides, Cyclic, Quinolinium Compounds, Random Allocation, Recombinant Proteins, T-Lymphocytes, Mice, Knockout, Neuroprotective Agents, Amino Acid Substitution, Cyclophilins, Mitochondrial Membrane Transport Proteins, Cell Proliferation, Hep G2 Cells

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