NDUFV2P1-driven modulation of mitochondrial and neuronal activities; implications to schizophrenia

Abstract

Schizophrenia (SZ) is a severe psychiatric disorder characterized by psychosis, cognitive deficits, and disrupted 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, whose alterations occur post-transcriptionally. We previously showed that the 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 cells lines (LCLs). In-silico analyses excluded small RNA interference with NDUFV2, implicating PG as an interfering factor. 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 function, altering {Delta}{psi}m, mitochondrial 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 a mechanistic pathway through which PG interferes with NDUFV2, leading to SZ-related mitochondrial and neuronal deficits, and suggests therapeutic potential for PG downregulation in diseases with bioenergetic impairments such as SZ.