Disrupted-in-schizophrenia 1 (DISC1) plays essential roles in mitochondria in collaboration with Mitofilin.
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 Ca(2+) 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.
Park
Young-Un
YU
Division of Molecular and Life Science, Department of Life Science, Biotechnology Research Center, Pohang University of Science and Technology, Pohang 790-784, Korea.
Jeong
Jaehoon
J
Lee
Haeryun
H
Mun
Ji Young
JY
Kim
Joung-Hun
JH
Lee
Jong Seo
JS
Nguyen
Minh Dang
MD
Han
Sung Sik
SS
Suh
Pann-Ghill
PG
Park
Sang Ki
SK
D000255:Adenosine Triphosphate / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D008995:Monoamine Oxidase / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009245:NADH Dehydrogenase / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D012559:Schizophrenia / Q000378:metabolism*; D020798:Two-Hybrid System Techniques
C412476:DISC1 protein, human; C088548:IMMT protein, human; D024101:Mitochondrial Proteins; D009124:Muscle Proteins; D009419:Nerve Tissue Proteins; D000255:Adenosine Triphosphate; D008995:Monoamine Oxidase; D009245:NADH Dehydrogenase; D002118:Calcium