Ben-Shachar, D.; Lapiro, Y.; Karry, R.; Binah, O.

Schizophrenia (SZ) is a severe mental disorder affecting emotion, cognitive and social functioning. Mitochondria are essential for neuronal function, synaptic plasticity, and behavior, all impaired in SZ. A major driver of mitochondrial dysfunction in SZ is Complex I, particularly its NDUFV2 core-subunit. We showed that NDUFV2 pseudogene (NDUFV2P1; PG) is upregulated in brain and peripheral cells of SZ patients and inversely correlates with NDUFV2 expression and mitochondrial respiration in Epstein-Barr-virus-transformed lymphocyte cell-lines (LCLs). In-silico analyses exclude small RNA interference with NDUFV2, implicating PG instead. To study PG effects on NDUFV2 expression, mitochondrial function, and neuronal activity, we modulated PG abundance in LCLs. PG overexpression in healthy-derived LCLs impaired mitochondrial {Delta}{Psi}m, network dynamics, and oxygen consumption, while PG downregulation in SZ-derived LCLs restored these parameters to normal levels. In rat cortical neurons, PG overexpression induced comparable mitochondrial disruptions alongside impaired synapse formation and reduced spontaneous neuronal firing. This study provides evidence for PG modulation of NDUFV2, leading to SZ-related mitochondrial and neuronal deficits, and suggests therapeutic potential for PG downregulation in bioenergetic impairments such as SZ.