# miR-214-3p exacerbates mitochondrial dysfunction in parkinson's disease: a multi-omics and mechanistic study

## TL;DR

This study shows that miR-214-3p worsens mitochondrial problems in Parkinson's disease, especially in dopaminergic cells by targeting GFM1.

## Contribution

The study identifies miR-214-3p's role in mitochondrial dysfunction and reveals a cell-type specific mechanism involving GFM1 in Parkinson's disease.

## Key findings

- miR-214-3p upregulation reduces GFM1, leading to mitochondrial bioenergetic impairment in dopaminergic cells.
- Restoring GFM1 reverses mitochondrial deficits and neuronal dysfunction caused by miR-214-3p.
- miR-214-3p impairs respiratory chain complexes in mouse neurons independently of GFM1.

## Abstract

Parkinson’s disease (PD) involves the loss of dopaminergic neurons, and prodromal PD exhibits elevated miR-214-3p, suggesting its role as a biomarker and pathogenic factor. This study investigated miR-214-3p’s effects on mitochondrial function in dopaminergic SH-SY5Y cells and mouse primary cortical neurons. In SH-SY5Y cells, proteomic/transcriptomic analyses and target prediction confirmed GFM1 as a direct target of miR-214-3p. miR-214-3p upregulation downregulated GFM1, causing severe mitochondrial bioenergetic impairment: increased reactive oxygen species (ROS), reduced oxygen consumption, diminished ATP production, and decreased respiratory chain complexes (RCC) I/IV expression. Critically, restoring GFM1 reversed these mitochondrial deficits and neuronal dysfunction. In mouse primary cortical neurons, miR-214-3p overexpression also impaired RCC I/IV but did not affect GFM1, revealing a cell type-dependent regulatory mechanism. These findings demonstrate that elevated miR-214-3p impairs mitochondrial function in a cell-specific manner. In dopaminergic cells, this damage is mediated by GFM1 downregulation, highlighting the miR-214-3p/GFM1 axis as a potential cell-type specific therapeutic target for PD and related dopaminergic neuronopathies.

The online version contains supplementary material available at 10.1007/s00221-026-07267-0.