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

Yi Fan Chen, Cheng Heng Kao, Ya Ting Chen, Chih Hao Wang, Chia Yu Wu, Ching Yen Tsai, Fu Chin Liu, Chu Wen Yang, Yau Huei Wei, Ming Ta Hsu, Shih Feng Tsai, Ting Fen Tsai

Research output: Contribution to journalArticlepeer-review

218 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1183-1194
Number of pages12
JournalGenes and Development
Issue number10
Publication statusPublished - May 15 2009
Externally publishedYes


  • Autophagy
  • Cisd2
  • Knockout mice
  • Mitochondria
  • Premature aging
  • Wolfram syndrome 2

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology


Dive into the research topics of 'Cisd2 deficiency drives premature aging and causes mitochondria-mediated defects in mice'. Together they form a unique fingerprint.

Cite this