Disrupted-in-schizophrenia 1 (DISC1) plays essential roles in mitochondria in collaboration with Mitofilin

Young Un Park, Jaehoon Jeong, Haeryun Lee, Ji Young Mun, Joung Hun Kim, Jong Seo Lee, Minh Dang Nguyen, Sung Sik Han, Pann Ghill Suh, Sang Ki Park

Research output: Contribution to journalArticle

96 Citations (Scopus)

Abstract

Disrupted-in-schizophrenia 1 (DISC1) has emerged as a schizophrenia- susceptibility gene affecting various neuronal functions. In this study, we characterized Mitofilin, a mitochondrial inner membrane protein, as a mediator of the mitochondrial function of DISC1. A fraction of DISC1 was localized to the inside of mitochondria and directly interacts with Mitofilin. A reduction in DISC1 function induced mitochondrial dysfunction, evidenced by decreased mitochondrial NADH dehydrogenase activities, reduced cellular ATP contents, and perturbed mitochondrial Ca2+ dynamics. In addition, deficiencies in DISC1 and Mitofilin induced a reduction in mitochondrial monoamine oxidase-A activity. The mitochondrial dysfunctions evoked by the deficiency of DISC1 were partially phenocopied by an overexpression of truncated DISC1 that is associated with schizophrenia in human. DISC1 deficiencies induced the ubiquitination of Mitofilin, suggesting that DISC1 is critical for the stability of Mitofilin. Finally, the mitochondrial dysfunction induced by DISC1 deficiency was partially reversed by coexpression of Mitofilin, confirming a functional link between DISC1 and Mitofilin for the normal mitochondrial function. According to these results, we propose that DISC1 plays essential roles for mitochondrial function in collaboration with a mitochondrial interacting partner, Mitofilin.

Original languageEnglish
Pages (from-to)17785-17790
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number41
DOIs
Publication statusPublished - 2010 Oct 12

Keywords

  • Calcium buffering
  • Hyperdopaminergia
  • IMMT
  • Mitochondrial dysfunctions
  • Psychiatric disorders

ASJC Scopus subject areas

  • General

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