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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2010-10, Vol.107 (41), p.17785-17790
• Main Authors: Park, Young-Un, Jeong, Jaehoon, Lee, Haeryun, Mun, Ji Young, Kim, Joung-Hun, Lee, Jong Seo, Nguyen, Minh Dang, Han, Sung Sik, Suh, Pann-Ghill, Park, Sang Ki
• Format: Article
• Language: English
• Subjects: Adenosine triphosphatase; Adenosine Triphosphate - metabolism; ATP; Biological Sciences; Calcium; Calcium (mitochondrial); Calcium - metabolism; Calcium signalling; Cell lines; Cellular differentiation; Dehydrogenases; DISC1 protein; Down regulation; Enzyme kinetics; Gene expression; HEK293 cells; HeLa cells; Humans; Immunohistochemistry; Immunoprecipitation; Inner membranes; Membrane proteins; Membranes; Mental disorders; Mitochondria; Mitochondria - metabolism; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; Monoamine Oxidase - metabolism; monoamines; Muscle Proteins - genetics; Muscle Proteins - metabolism; NADH dehydrogenase; NADH Dehydrogenase - drug effects; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurons; Proteins; Schizophrenia; Schizophrenia - metabolism; Studies; Two-Hybrid System Techniques; ubiquitination; Yeasts
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1004361107

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.