Parkinson's disease (PD) is one of the fastest growing neurodegenerative diseases and severely affects quality of life and lifespan. PD is caused by degeneration of dopaminergic neurons in the substantia nigra of the midbrain; the pathomechanism appears to be linked to defects in iron metabolism and mitochondrial quality control. CISD1 is a dimeric 2Fe-2S cluster-containing protein on the outer mitochondrial membrane which is an important target of PINK1/Parkin-mediated mitochondrial quality control; a pathway severely compromised in PD. CISD1 is characterized by its labile Fe/S cluster which can be transferred to other proteins under certain conditions such as oxidative stimuli and iron availability. 

We found that CISD1 dimerizes more in human dopaminergic neurons from patients suffering from autosomal-recessive Parkinson’s disease caused by PINK1 mutation and in Pink1 mutant Drosophila flies. Deleting CISD1 expression in mutated flies rescued the defects in mitochondrial shape and function and normalized climbing ability and lifespan of mutant flies. These results implied that dimerized CISD1 is part of the toxic phenotype elicited by Pink1 loss of function. Using Nanobit technology, we discovered that CISD1 lacking its Fe/S cluster is more prone to dimerization and probably represents the increased dimer identified in our human and fly models of PD. In line with this, overexpression of an iron-depleted form of CISD1 was detrimental in mammalian cells and flies. We therefore hypothesize that accumulation of iron-less CISD1 is a catalyst for the progression of PD and its severity.