# Single-cell transcriptome-wide Mendelian randomization identifies mitochondrial targets in immune cells for Major Depressive Disorder

## TL;DR

This study finds that specific mitochondrial genes in immune cells are linked to major depressive disorder, offering new diagnostic and treatment targets.

## Contribution

The study identifies five mitochondrial genes in immune cells with causal effects on depression risk using Mendelian randomization and validates findings in a rat model.

## Key findings

- Five mitochondria-related genes (HK2, NDUFS4, NEU1, SOD1, UCP2) show causal effects on MDD risk in immune cells.
- UCP2 and SOD1 are risk factors, while HK2, NDUFS4, and NEU1 are protective in specific immune cell types.
- Findings were validated in a rat model and showed diagnostic potential in an independent cohort.

## Abstract

A critical need exists for objective biomarkers and novel therapeutic targets in major depressive disorder (MDD). Although dysfunction in mitochondrial immunometabolism is implicated in MDD, the specific causal genes suitable for clinical translation remain largely unidentified. This study aimed to bridge this gap by identifying mitochondria-related genes that have a causal impact on MDD risk through their expression in specific immune cells.

We integrated multi-omics data with machine learning to pinpoint key mitochondria-related energy metabolism genes (MEMRGs) linked to immune cell infiltration, assessed via ssGSEA and CIBERSORT algorithms. Cell-type-specific two-sample Mendelian randomization (MR) was employed to evaluate causal relationships between gene expression and MDD risk. Findings were validated in a chronic unpredictable mild stress (CUMS) rat model.

Our analysis identified five genes—HK2, NDUFS4, NEU1, SOD1, and UCP2—whose expression in distinct immune populations had significant causal effects on MDD risk. Notably, HK2, NDUFS4, and NEU1 were identified as protective factors, while UCP2 and SOD1 were risk factors in specific cell types. The clinical relevance of this panel was supported by its diagnostic performance in an independent cohort, and the upregulation of the principal risk gene, UCP2, was confirmed in the hippocampus of CUMS rats.

This study provides robust genetic evidence establishing a causal link between the expression of specific mitochondrial genes in immune cells and the risk of MDD. By prioritizing UCP2, SOD1, HK2, NDUFS4, and NEU1, our findings highlight novel, immune-mediated pathways in depression and nominate promising targets for future diagnosis and therapeutic intervention.