# Targeting NME3 to Restore Mitochondrial Fission‐Fusion Balance Defines a Novel Disease‐Modifying Strategy for Parkinson's Disease

## TL;DR

This study shows that restoring mitochondrial balance by targeting NME3 can protect neurons and improve symptoms in Parkinson's disease models.

## Contribution

NME3 is identified as a novel regulator of mitochondrial dynamics in Parkinson's disease, offering a new therapeutic strategy.

## Key findings

- NME3 deficiency disrupts mitochondrial balance and increases ROS, leading to neuronal damage.
- Pharmacological inhibition of Drp1 or NME3 overexpression restores mitochondrial function and protects neurons.
- NME3-targeted strategies show promise as disease-modifying therapies for Parkinson's disease.

## Abstract

Parkinson's disease (PD) lacks effective disease‐modifying therapies, despite mitochondrial dysfunction being a key pathogenic factor. This study aimed to identify novel regulators of mitochondrial dynamics and explore their therapeutic relevance.

Transcriptomic analysis was conducted on the substantia nigra (SN) of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced PD mice. SN‐specific lentiviral knockdown or overexpression of nucleoside diphosphate kinase 3 (NME3) was performed in mice. Motor behavior, dopaminergic neuron survival, mitochondrial ultrastructure, and reactive oxygen species (ROS) levels were assessed. Mitochondrial fission was pharmacologically inhibited using the Drp1 inhibitor Mdivi‐1.

RNA sequencing revealed a marked reduction of Nme3 in the SN of MPTP‐treated mice. Nme3 knockdown in healthy mice induced PD‐like motor deficits and dopaminergic neurodegeneration, mimicking the MPTP model. Mechanistically, NME3 deficiency disrupted mitochondrial fission‐fusion balance, causing abnormal mitochondrial morphology, excessive ROS production, and neuronal injury. Mdivi‐1 treatment significantly alleviated mitochondrial dysfunction and neurotoxicity. Conversely, SN‐specific Nme3 overexpression in MPTP‐treated mice improved motor performance and preserved dopaminergic neurons by suppressing pathological mitochondrial fission.

NME3 is a previously unrecognized regulator of mitochondrial dynamics and a critical contributor to PD pathogenesis. Restoring mitochondrial fission‐fusion balance through genetic or pharmacological approaches provides neuroprotection, highlighting NME3 as a promising target for disease‐modifying PD therapies.

NME3 deficiency disrupts mitochondrial fission‐fusion balance, causing neuronal damage via ROS. Pharmacological Drp1 inhibition (Mdivi‐1) or substantia nigra‐specific NME3 overexpression restores mitochondrial equilibrium, prevents dopaminergic neuron loss, and alleviates motor deficits in PD models. This identifies NME3‐targeted strategies as novel disease‐modifying therapies for Parkinson's disease.