Iron-sulfur cluster loss in mitochondrial CISD1 mediates PINK1 loss-of-function phenotypes

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 <i>Drosophila</i> ortholog of CISD1, and a mutant Cisd incapable of binding the iron-sulfur cluster in <i>Drosophila</i> 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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Publication Details

Journal
eLife
Published
2024-08-19
DOI
https://doi.org/10.7554/elife.97027
Citations
8
Primary Topic
Amyotrophic Lateral Sclerosis Research
Type
article
Field-Weighted Citation Impact
2.95

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article

Iron-sulfur cluster loss in mitochondrial CISD1 mediates PINK1 loss-of-function phenotypes

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8 citations
eLife
Amyotrophic Lateral Sclerosis Research
2.95
article

Iron-sulfur cluster loss in mitochondrial CISD1 mediates PINK1 loss-of-function phenotypes

Patrick Ziegler, Bernhard Michalke, Eva-Maria Hanschmann, Liliana Rojas-Charry, Axel Methner, Sara Bitar, Timo Baumann, Giuseppe Arena, Thomas Schettgen, Rejko Krueger, Isabella Eva Randerath, Vivek Venkataramani, Majd Abusaada, Christopher R. Weber, Li Zhang
article en
8 citations

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 <i>Drosophila</i> ortholog of CISD1, and a mutant Cisd incapable of binding the iron-sulfur cluster in <i>Drosophila</i> 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.

eLifeVol. 13
Centre Hospitalier de Luxembourg (LU), University of Luxembourg (LU), Johannes Gutenberg University Mainz (DE), Center for Environmental Health (US), Helmholtz Zentrum München (DE), University Medical Center of the Johannes Gutenberg University Mainz (DE), Comprehensive Cancer Center Mainfranken (DE), Luxembourg Institute of Health (LU), Universitätsklinikum Würzburg (DE), Institute for Molecular Medicine (US), RWTH Aachen University (DE)
Université du Luxembourg, Deutsche Forschungsgemeinschaft, Fonds National de la Recherche Luxembourg, Universität zu Lübeck
Openalex Percentile: Top 8%
Amyotrophic Lateral Sclerosis Research
2.95
DOIOpen Access PDFOpenAlex
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