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Molecular Neurodegeneration
Published in: Molecular Neurodegeneration 1/2024

Open Access 01-12-2024 | Parkinson's Disease | Research article

Mitochondrial CISD1/Cisd accumulation blocks mitophagy and genetic or pharmacological inhibition rescues neurodegenerative phenotypes in Pink1/parkin models

Authors: Aitor Martinez, Alvaro Sanchez-Martinez, Jake T. Pickering, Madeleine J. Twyning, Ana Terriente-Felix, Po-Lin Chen, Chun-Hong Chen, Alexander J. Whitworth

Published in: Molecular Neurodegeneration | Issue 1/2024

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Abstract

Background

Mitochondrial dysfunction and toxic protein aggregates have been shown to be key features in the pathogenesis of neurodegenerative diseases, such as Parkinson’s disease (PD). Functional analysis of genes linked to PD have revealed that the E3 ligase Parkin and the mitochondrial kinase PINK1 are important factors for mitochondrial quality control. PINK1 phosphorylates and activates Parkin, which in turn ubiquitinates mitochondrial proteins priming them and the mitochondrion itself for degradation. However, it is unclear whether dysregulated mitochondrial degradation or the toxic build-up of certain Parkin ubiquitin substrates is the driving pathophysiological mechanism leading to PD. The iron-sulphur cluster containing proteins CISD1 and CISD2 have been identified as major targets of Parkin in various proteomic studies.

Methods

We employed in vivo Drosophila and human cell culture models to study the role of CISD proteins in cell and tissue viability as well as aged-related neurodegeneration, specifically analysing aspects of mitophagy and autophagy using orthogonal assays.

Results

We show that the Drosophila homolog Cisd accumulates in Pink1 and parkin mutant flies, as well as during ageing. We observed that build-up of Cisd is particularly toxic in neurons, resulting in mitochondrial defects and Ser65-phospho-Ubiquitin accumulation. Age-related increase of Cisd blocks mitophagy and impairs autophagy flux. Importantly, reduction of Cisd levels upregulates mitophagy in vitro and in vivo, and ameliorates pathological phenotypes in locomotion, lifespan and neurodegeneration in Pink1/parkin mutant flies. In addition, we show that pharmacological inhibition of CISD1/2 by rosiglitazone and NL-1 induces mitophagy in human cells and ameliorates the defective phenotypes of Pink1/parkin mutants.

Conclusion

Altogether, our studies indicate that Cisd accumulation during ageing and in Pink1/parkin mutants is a key driver of pathology by blocking mitophagy, and genetically and pharmacologically inhibiting CISD proteins may offer a potential target for therapeutic intervention.

Graphical Abstract

Appendix
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Metadata
Title
Mitochondrial CISD1/Cisd accumulation blocks mitophagy and genetic or pharmacological inhibition rescues neurodegenerative phenotypes in Pink1/parkin models
Authors
Aitor Martinez
Alvaro Sanchez-Martinez
Jake T. Pickering
Madeleine J. Twyning
Ana Terriente-Felix
Po-Lin Chen
Chun-Hong Chen
Alexander J. Whitworth
Publication date
01-12-2024
Publisher
BioMed Central
Published in
Molecular Neurodegeneration / Issue 1/2024
Electronic ISSN: 1750-1326
DOI
https://doi.org/10.1186/s13024-024-00701-3

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