Abstract
Reproductive organs and developing tissues have high energy demands that require metabolic functions primarily supported by mitochondria function. The highly conserved CISD/NEET iron-sulfur (Fe-S) protein family regulates iron and reactive oxygen homeostasis, both of which are important for mitochondrial function. Disruption of iron and reactive oxygen homeostasis typically leads to detrimental effects. In humans, CISD dysfunction is associated with human health issues including Wolfram syndrome 2. Using C. elegans, we previously determined that the cisd-1, cisd-3.1 and cisd-3.2 have an overlapping role in the regulation of physiological germline apoptosis through the canonical programmed cell death pathway. Here, we isolated the cisd-3.2(pnIs68) mutant that resulted in physiological and fitness defects including germline abnormalities that are associated with abnormal stem cell niche and disrupted formation of bivalent chromosomes. The cisd-3.2(pnIs68) mutation led to complete disruption of the cisd-3.2 gene expression and a decrease in expression of genetically intact cisd-1 and cisd-3.1 genes suggesting an indirect impact of the cisd-3.2(pnIs68) allele. The CISD-3.2 and CISD-3.1 proteins localize to the mitochondria in many tissues throughout development. The cisd-3.2(pnIs68) mutant displays phenotypes associated with mitochondrial dysfunction, including disruption of the mitochondrial network within the germline. These results further support the idea that the CISD protein family is required for mitochondrial function that supports important functions in animals including overall fitness and germline viability.
Highlights
The highly conserved NEET proteins represented in humans as mitoNEET/CISD1, NAF-1/ CISD2, and MiNT/Miner2/CISD3 constitute a novel class of iron-sulfur cluster proteins
We previously determined that knock-down of cisd-3.1 or cisd-3.2 through RNAi led to animals with various germline defects including a decreased number of oocytes, distal tip cell (DTC) migration defects (Mig phenotype), and an increase in the number of cell corpses within the cisd-3.2 is essential for germline function germline [16]
We determined that deletion of the cisd-1 gene and knock-down of cisd-3.1 and cisd-3.2 via RNAi resulted in various germline abnormalities including an increase in cell corpses within the adult germline and abnormal distal tip cell migration [16]
Summary
The highly conserved NEET proteins represented in humans as mitoNEET/CISD1, NAF-1/ CISD2, and MiNT/Miner2/CISD3 constitute a novel class of iron-sulfur cluster proteins. The human MiNT protein has been crystalized and revealed to be a monomer with two distinct [2Fe-2S] cluster-binding domains [5] Both MitoNEET/CISD1 and NAF1/CISD2 have a role in autophagy and apoptosis. We previously determined that knock-down of cisd-3.1 or cisd-3.2 through RNAi led to animals with various germline defects including a decreased number of oocytes, distal tip cell (DTC) migration defects (Mig phenotype), and an increase in the number of cell corpses within the cisd-3.2 is essential for germline function germline [16] Combined, these studies support the idea that the CISD proteins in C. elegans have a role in germline function and metabolic processes. This work further supports the role the CISD family has in mitochondrial functions and proper germ cell differentiation in the germline of C. elegans
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