Mitochondrial-Targeting Vitamin B₃ Ameliorates the Phenotypes of Parkinson's Disease In Vitro and In Vivo by Restoring Mitochondrial Function

Parkinson's disease (PD) is the second most common neurodegenerative disease and is characterized by progressive dopaminergic neuron loss, which affects millions of people worldwide, especially elderly individuals. Mitochondrial dysfunction is believed to be one crucial causative factor of PD. Therefore, restoring mitochondrial function is highly recommended for the treatment of PD. Herein, it is found that vitamin B₃ (VB₃) protects the dopaminergic cell line SH-SY5Y against rotenone-induced apoptosis by restoring mitochondrial dysfunction. To further improve the efficacy, a derivative of VB₃, mitochondrial-targeting VB₃ (Mito-VB₃), is developed. It is demonstrated that Mito-VB₃ rescues SH-SY5Y cells from the neurotoxicity of oxidative stress. More importantly, Mito-VB₃ ameliorates the phenotypes of the Drosophila PD model. Mechanistically, Mito-VB₃ enhances nicotinamide adenine dinucleotide (NAD⁺) levels, reduces ROS generation, elevates ATP levels, and restores mitochondrial membrane potential. Meanwhile, Mito-VB₃ promotes mitochondrial biogenesis by activating the NAD⁺/SIRT1/PGC1α pathway. In summary, the results demonstrate that Mito-VB₃ displays remarkable neuroprotective effects in the cell and Drosophila PD models and that Mito-VB₃ might serve as a potential therapeutic candidate for the treatment of PD and other mitochondrial dysfunction-related diseases.