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

Abstract

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 B 3 (VB 3 ) protects the dopaminergic cell line SH-SY5Y against rotenone-induced apoptosis by restoring mitochondrial dysfunction. To further improve the efficacy, a derivative of VB 3 , mitochondrial-targeting VB 3 (Mito-VB 3 ), is developed. It is demonstrated that Mito-VB 3 rescues SH-SY5Y cells from the neurotoxicity of oxidative stress. More importantly, Mito-VB 3 ameliorates the phenotypes of the Drosophila PD model. Mechanistically, Mito-VB 3 enhances nicotinamide adenine dinucleotide (NAD + ) levels, reduces ROS generation, elevates ATP levels, and restores mitochondrial membrane potential. Meanwhile, Mito-VB 3 promotes mitochondrial biogenesis by activating the NAD + /SIRT1/PGC1𝜶 pathway. In summary, the results demonstrate that Mito-VB 3 displays remarkable neuroprotective effects in the cell and Drosophila PD models and that Mito-VB 3 might serve as a potential therapeutic candidate for the treatment of PD and other mitochondrial dysfunction-related diseases.