Iron-sulfur cluster loss in mitochondrial CISD1 mediates PINK1 loss-of-function phenotypes
- Johannes Gutenberg University of Mainz, Germany
- RWTH Aachen University, Germany
- University Hospital Würzburg, Germany
- Helmholtz Zentrum München, Germany
- University of Duisburg-Essen, Germany
- University of Luxembourg, Luxembourg
Abstract
Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra of the midbrain. Familial cases of PD are often caused by mutations of PTEN-induced kinase 1 (PINK1) and the ubiquitin ligase Parkin, both pivotal in maintaining mitochondrial quality control. CISD1, a homodimeric mitochondrial iron-sulfur-binding protein, is a major target of Parkin-mediated ubiquitination. We here discovered a heightened propensity of CISD1 to form dimers in Pink1 mutant flies and in dopaminergic neurons from PINK1 mutation patients. The dimer consists of two monomers that are covalently linked by a disulfide bridge. In this conformation CISD1 cannot coordinate the iron-sulfur cofactor. Overexpressing Cisd, the Drosophila orthologue of CISD1, and a mutant Cisd incapable of binding the iron-sulfur cluster in Drosophila reduced climbing ability and lifespan. This was more pronounced with mutant Cisd and aggravated in Pink1 mutant flies. Complete loss of Cisd, in contrast, rescued all detrimental effects of Pink1 mutation on climbing ability, wing posture, dopamine levels, lifespan, and mitochondrial ultrastructure. Our results suggest that Cisd, probably iron-depleted Cisd, operates downstream of Pink1 shedding light on PD pathophysiology and implicating CISD1 as a potential therapeutic target.
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All data generated or analysed during this study are included in the manuscript and supporting files
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Funding
Deutsche Forschungsgemeinschaft (445683311)
- Axel Methner
Deutsche Forschungsgemeinschaft (461705066)
- Vivek Venkataramani
Fonds National de la Recherche Luxembourg (C21/BM/15850547/PINK1-DiaPDs)
- Giuseppe Arena
Deutsche Forschungsgemeinschaft (461705066)
- Axel Methner
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: Induced pluripotent stem cells (iPSCs) from two PD patients carrying the p.Q456X mutation in PINK1 were obtained from the University of Lübeck. Both participants signed a written informed consent according to the Declaration of Helsinki. Ethical approval for conducting iPSC studies in Krüger's lab was granted by the National Committee for Ethics in Research, Luxembourg (Comité National d'Ethique de Recherche; CNER #201411/05).
Copyright
© 2024, Bitar et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Iron-sulfur cluster loss in mitochondrial CISD1 mediates PINK1 loss-of-function phenotypes
eLife 13:e97027.
https://doi.org/10.7554/eLife.97027
