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

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AimsParkinson'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.MethodsTranscriptomic 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.ResultsRNA 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.ConclusionNME3 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.

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