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Bitar, S.* ; Baumann, T.* ; Weber, C.* ; Abusaada, M.* ; Rojas-Charry, L.* ; Ziegler, P.* ; Schettgen, T.* ; Randerath, I.E.* ; Venkataramani, V.* ; Michalke, B. ; Hanschmann, E.M.* ; Arena, G.* ; Krueger, R.* ; Zhang, L.* ; Methner, A.*

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

eLife 13:e97027 (2024)
Verlagsversion DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter D. Melanogaster ; Cell Biology ; Human ; Mouse ; Neuroscience; Element Binding-protein; Responsive Element; Membrane Protein; Regulatory Proteins; Parkinsons-disease; Mitoneet; Drosophila; Identification; Metabolism; Aconitase
ISSN (print) / ISBN 2050-084X
e-ISSN 2050-084X
Zeitschrift eLife
Quellenangaben Band: 13, Heft: , Seiten: , Artikelnummer: e97027 Supplement: ,
Verlag eLife Sciences Publications
Verlagsort Sheraton House, Castle Park, Cambridge, Cb3 0ax, England
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Research Unit Analytical BioGeoChemistry (BGC)
Förderungen Fonds National de la Recherche Luxembourg
Deutsche Forschungsgemeinschaft