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PMID:19451219

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Citation

Chen, YF, Kao, CH, Chen, YT, Wang, CH, Wu, CY, Tsai, CY, Liu, FC, Yang, CW, Wei, YH, Hsu, MT, Tsai, SF and Tsai, TF (2009) Cisd2 deficiency drives premature aging and causes mitochondria-mediated defects in mice. Genes Dev. 23:1183-94

Abstract

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.

Links

PubMed PMC2685531 Online version:10.1101/gad.1779509

Keywords

Aging/genetics; Aging/metabolism; Aging, Premature/genetics; Aging, Premature/physiopathology; Animals; Autophagy; Carrier Proteins/metabolism; Disease Models, Animal; Female; Glucose Intolerance/genetics; Glucose Intolerance/physiopathology; Humans; Longevity/genetics; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria/metabolism; Mitochondrial Proteins/genetics; Mitochondrial Proteins/metabolism; Muscles/pathology; Nerve Tissue Proteins/deficiency; Nerve Tissue Proteins/metabolism; Neurons/pathology; Optic Nerve Diseases/genetics; Optic Nerve Diseases/physiopathology; Wolfram Syndrome/physiopathology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:CISD2

involved_in

GO:0000422: autophagy of mitochondrion

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:CISD2

involved_in

GO:0010259: multicellular organism aging

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:CISD2

located_in

GO:0005789: endoplasmic reticulum membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:CISD2

located_in

GO:0005741: mitochondrial outer membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete


See also

References

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