Cisd2 deficiency drives premature aging and causes mitochondria-mediated defects in mice

Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 112, Taiwan.
Genes & development (Impact Factor: 10.8). 06/2009; 23(10):1183-94. DOI: 10.1101/gad.1779509
Source: PubMed


CISD2, the causative gene for Wolfram syndrome 2 (WFS2), is a previously uncharacterized novel gene. Significantly, the CISD2 gene is located on human chromosome 4q, where a genetic component for longevity maps. Here we show for the first time that CISD2 is involved in mammalian life-span control. Cisd2 deficiency in mice causes mitochondrial breakdown and dysfunction accompanied by autophagic cell death, and these events precede the two earliest manifestations of nerve and muscle degeneration; together, they lead to a panel of phenotypic features suggestive of premature aging. Our study also reveals that Cisd2 is primarily localized in the mitochondria and that mitochondrial degeneration appears to have a direct phenotypic consequence that triggers the accelerated aging process in Cisd2 knockout mice; furthermore, mitochondrial degeneration exacerbates with age, and the autophagy increases in parallel to the development of the premature aging phenotype. Additionally, our Cisd2 knockout mouse work provides strong evidence supporting an earlier clinical hypothesis that WFS is in part a mitochondria-mediated disorder; specifically, we propose that mutation of CISD2 causes the mitochondria-mediated disorder WFS2 in humans. Thus, this mutant mouse provides an animal model for mechanistic investigation of Cisd2 protein function and help with a pathophysiological understanding of WFS2.

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Available from: Chih-Hao Wang
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    • "Mitochondrial (mito)NEET (mNT; encoded by CISD1) and NAF-1 (encoded by CISD2) are the most studied representatives of the three-member NEET-family in humans. They have been implicated in a number of pathologies, including neural development, obesity, diabetes and aging, and are rapidly gaining prominence as targets for cancer therapy (Bai et al., 2015; Boucquey et al., 2006; Chen et al., 2009b,c, 2010; Liu et al., 2014; Tamir et al., 2015; Wang et al., 2014a,b; Wiley et al., 2013; Wu et al., 2012). NAF-1 is located at the interface of the ER and mitochondria, anchored to the Ca 2+ channel inositol 1,4,5- triphosphate receptor and is necessary for BCL-2-mediated suppression of autophagy and control of Ca 2+ homeostasis (Chang et al., 2012a,b, 2010; Du et al., 2015). "
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    • "Cisd2 knockout mice exhibit neurodegeneration along with shortened lifespan (Chen et al., 2009). These mice also have mitochondrial degeneration (Chen et al., 2009), suggesting that CISD2 is important for mitochondrial integrity and that mitochondrial dysfunction might contribute to the pathology of WFS2. Despite these and other advances in understanding CISD2, its function has not been fully resolved. "
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    ABSTRACT: Wolfram syndrome (WFS) is a progressive neurodegenerative disease characterized by diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. WFS1 and WFS2 are caused by recessive mutations in the genes Wolfram Syndrome 1 (WFS1) and CDGSH iron sulfur domain 2 (CISD2), respectively. To explore the function of CISD2, we performed genetic studies in flies with altered expression of its Drosophila orthologue, cisd2. Surprisingly, flies with strong ubiquitous RNAi-mediated knockdown of cisd2 had no obvious signs of altered life span, stress resistance, locomotor behavior or several other phenotypes. We subsequently found in a targeted genetic screen, however, that altered function of cisd2 modified the effects of overexpressing the fly orthologues of two lysosomal storage disease genes, palmitoyl-protein thioesterase 1 (PPT1 in humans, Ppt1 in flies) and ceroid-lipofuscinosis, neuronal 3 (CLN3 in humans, cln3 in flies), on eye morphology in flies. We also found that cln3 modified the effects of overexpressing Ppt1 in the eye and that overexpression of cln3 interacted with a loss of function mutation in cisd2 to disrupt locomotor ability in flies. Follow-up multi-species bioinformatic analyses suggested that a gene network centered on CISD2, PPT1 and CLN3 might impact disease through altered carbohydrate metabolism, protein folding and endopeptidase activity. Human genetic studies indicated that copy number variants (duplications and deletions) including CLN3, and possibly another gene in the CISD2/PPT1/CLN3 network, are over-represented in individuals with developmental delay. Our studies indicate that cisd2, Ppt1 and cln3 function in concert in flies, suggesting that CISD2, PPT1 and CLN3 might also function coordinately in humans. Further, our studies raise the possibility that WFS2 and some lysosomal storage disorders might be influenced by common mechanisms and that the underlying genes might have previously unappreciated effects on developmental delay.
    Full-text · Article · Apr 2014 · Biology Open
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    • "altered mitochondrial function at least partially due to depletion of Cox4i1 , and Cox4i1 knockdown itself results in accelerated senescence in vitro . Overall , our data are consis - tent with recent findings from in vivo mouse models of mitochondrial dysfunction and unbal - anced ROS homeostasis ( Trifunovic et al . 2004 ; Laurent et al . 2008 ; Chen et al . 2009 ; Liu et al . 2009 ; Loh et al . 2009 ; Reilly et al . 2010 ; Sahin et al . 2011 ) and expand the p53 and mitochondrial axis of aging with the addition of new players , TAp73 and Cox4i1 ."
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