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

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 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.IMMT | mitochondrial dysfunctions | hyperdopaminergia | calcium buffering | psychiatric disorders

CHCM1/CHCHD6, Novel Mitochondrial Protein Linked to Regulation of Mitofilin and Mitochondrial Cristae Morphology

“…To date, detailed characterization of mitofilin interactions with two other proteins, including DISC1 (disrupted-in-schizophrenia 1) and CHCHD3, has been reported (13,14). DISC1 is linked to neurodevelopment and believed to be important for mitofilin stability (13), whereas CHCHD3 is linked to maintaining mitochondrial cristae morphology (14).…”

Disrupted in schizophrenia 1 (DISC1) is a constituent of the mammalian mitochondrial contact site and cristae organizing system (MICOS) complex, and is essential for oxidative phosphorylation

“…DISC1 acts as scaffold binding a number of other proteins. In mitochondria, it has been shown to interact with two main partners: Mic60/Mitofilin, with whom DISC1 collaborates in the maintenance of mitochondrial integrity (7), and the Miro-TRAK complex, with whom modulates mitochondrial motility (9,10). A third interacting partner of DISC1 in the mitochondria has also been identified, Mic25/CHCM1/Coiled-coil-Helix-Coiled-coilHelix Domain Containing (CHCHD)6 (from now on, Mic25/ CHCHD6), but the nature and the functional relevance of this interaction has not been described yet (11).…”

Perineuronal nets protect fast-spiking interneurons against oxidative stress

“…S1). Power spectrum analysis of the extracellular recordings revealed prominent β oscillations (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28) accompanied by smaller γ oscillations (30-60 Hz), reflecting rhythmic neuronal synchronization at these frequencies (Fig. S1).…”

“…Oxidative stress and decreased levels of the endogenous antioxidant and redox regulator glutathione (GSH) are observed in the prefrontal cortex of patients (18)(19)(20). Therefore, redox dysregulation via impaired GSH synthesis (21,22) or abnormal function of proteins encoded by other susceptibility genes [i.e., proline dehydrogenase (oxidase) 1 (PRODH), disrupted in schizophrenia 1 (DISC1), D-amino acid oxidase activator (DAOA or G72), dystrobrevin binding protein 1 (DTNBP1)] (23)(24)(25)(26)(27) could, together with oxidative stress generated by environmental insults, contribute to the pathophysiology of these disorders (28,29).…”