Abstract

Disrupted in Schizophrenia-1 (DISC1) has been associated with a broad spectrum of mental disorders. DISC1 is a multi-compartmentalized protein found in the cytoplasm, centrosome, nuclei and mostly enriched in mitochondria. In order to shed light on DISC1 mitochondrial function, we have studied its topology within the organelle. We show in here that in mammals DISC1 resides in the ‘Mitochondrial contact site and Cristae Organizing system’ (MICOS) complex, involved in cristae organization. DISC1 knockdown in SH-SY5Y cells causes MICOS disassembly and fragmentation of the mitochondrial morphology network. Moreover, DISC1 depleted cells have decreased mitochondrial DNA (mtDNA) content and steady state levels of oxidative phosphorylation (OXPHOS) subunits. As a consequence, OXPHOS complexes and supercomplexes are partially disassembled in DISC1 knockdown cells, which suffer severe bioenergetic defects, evidenced by impaired oxygen consumption, adenosine triphosphate synthesis and mitochondrial membrane potential. Transfection of recombinant full-length human DISC1 restores MICOS complex assembly and rescues OXPHOS function, meanwhile overexpression of the DISC1 truncated form Δ597-854, known to be pathogenic, fails to rescue the bioenergetic impairment caused by DISC1 knockdown. These results should contribute to reveal DISC1 physiological function and potential pathogenic role in severe mental illnesses.

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