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Iron-sulfur cluster loss in mitochondrial CISD1 mediates PINK1 loss-of-function phenotypes.
- Source :
-
ELife [Elife] 2024 Aug 19; Vol. 13. Date of Electronic Publication: 2024 Aug 19. - Publication Year :
- 2024
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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 ortholog 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.<br />Competing Interests: SB, TB, CW, MA, LR, PZ, TS, IR, VV, BM, EH, GA, RK, LZ, AM No competing interests declared<br /> (© 2024, Bitar et al.)
- Subjects :
- Animals
Humans
Drosophila melanogaster genetics
Drosophila melanogaster metabolism
Protein Serine-Threonine Kinases metabolism
Protein Serine-Threonine Kinases genetics
Phenotype
Parkinson Disease genetics
Parkinson Disease metabolism
Dopaminergic Neurons metabolism
Loss of Function Mutation
Mitochondrial Proteins metabolism
Mitochondrial Proteins genetics
Drosophila Proteins genetics
Drosophila Proteins metabolism
Iron-Sulfur Proteins genetics
Iron-Sulfur Proteins metabolism
Mitochondria metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2050-084X
- Volume :
- 13
- Database :
- MEDLINE
- Journal :
- ELife
- Publication Type :
- Academic Journal
- Accession number :
- 39159312
- Full Text :
- https://doi.org/10.7554/eLife.97027