# ERVWE1 Impairs Mitochondrial Homeostasis and Promotes Neuronal Apoptosis via the miR-27b-3p/BNIP3 Axis in Schizophrenia

## TL;DR

This study shows how a retroviral protein, ERVWE1, disrupts mitochondria in brain cells, leading to cell death in schizophrenia through a specific molecular pathway.

## Contribution

The study identifies a novel molecular pathway involving ERVWE1, miR-27b-3p, and BNIP3 in schizophrenia-related mitochondrial dysfunction and neuronal apoptosis.

## Key findings

- BNIP3 expression is elevated in schizophrenia brain tissues and correlates with ERVWE1 levels.
- ERVWE1 impairs mitochondrial function by suppressing miR-27b-3p, leading to increased BNIP3 and neuronal apoptosis.
- Mitochondrial defects include reduced mtDNA copy number and increased permeability transition pore opening.

## Abstract

Schizophrenia is a severe neurodevelopmental disorder with a complex and largely unresolved pathogenesis. Accumulating evidence indicates that mitochondrial dysfunction is a consistent pathological hallmark of schizophrenia, suggesting that impaired mitochondrial homeostasis may represent a convergent mechanism underlying disease vulnerability. BCL2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3) is a critical regulator of mitochondrial integrity and apoptosis. However, its role in schizophrenia has not yet been elucidated. Human endogenous retroviruses W family envelope (ERVWE1) has been implicated as a potential risk factor in schizophrenia, but the molecular mechanisms by which it contributes to neuronal pathology remain poorly understood. In this study, we investigated whether ERVWE1 induces mitochondrial dysfunction and neuronal apoptosis through the regulation of BNIP3. Bioinformatic analysis of the public dataset GSE53987 revealed significantly elevated BNIP3 expression in the brain tissues of patients with schizophrenia, accompanied by enrichment of mitochondria-related pathways. Consistently, BNIP3 expression was also increased in the peripheral blood of schizophrenia patients and positively correlated with ERVWE1 levels. Mechanistically, ERVWE1 upregulated BNIP3 expression by suppressing miR-27b-3p, a microRNA that directly targets BNIP3. The resulting increase in BNIP3 led to marked mitochondrial structural and functional impairment, characterized by reduced mitochondrial aspect ratio, enhanced mitochondria permeability transition pore (mPTP) opening, and decreased mitochondrial DNA (mtDNA) copy number. These mitochondrial defects subsequently triggered cytochrome c release into the cytosol, activating the intrinsic mitochondrial apoptotic pathway. Collectively, this study provides the first evidence that the ERVWE1/miR-27b-3p/BNIP3 axis contributes to mitochondrial dysfunction and neuronal apoptosis in schizophrenia. Our findings identify a previously unrecognized molecular pathway linking endogenous retroviral activity to mitochondrial pathology, offering novel insights into the mechanisms and potential therapeutic targets for schizophrenia.