Nitrite administration ameliorates mitochondrial bioenergetics and is neuroprotective in cellular and vertebrate models of Parkinson's disease

AimsNitrite oral administration has been proposed as a therapeutic avenue in cardiac ischemia due to its ability to decrease mitochondrial production of reactive oxygen species (ROS), via transient inhibition of respiratory complex I (C-I). Augmented ROS and mitochondrial C-I dysfunction are also hallmarks of Parkinson’s disease (PD), a chronic neurodegenerative disorder. Here we aimed to explore the neuroprotective capacity of nitrite in cellular and animal models of PD. MethodsWe modeled PD in dopaminergic neuronal cell lines (SH-SY5Y) and in zebrafish embryos using the parkinsonian toxin MPP+ and we used human fibroblasts derived from genetic PD patients harboring mutations in the LRRK2 gene. We pre-treated our specimens with nitrite and investigated the neuroprotective effects on cell viability, mitochondrial bioenergetics and motor functions.ResultsIn dopaminergic neurons, nitrite administration ameliorates MPP+ induced cell death. Bioenergetics analysis indicates that MPP+ perturbs mitochondrial respiration and this defect is reversed by nitrite administration. In zebrafish nitrite pre-treatment ameliorates locomotor activity after MPP+ exposure, improves viability, and reduces dopaminergic neuron loss in the brain. On a molecular level, the physiological effects of nitrite are mediated by nitrosation of cysteine residues in proteins, as evidenced by specific labeling with fluorescent maleimide derivatives after Cu++/ascorbate reduction of nitrosothiols. Finally, nitrite administration improves mitochondrial respiration efficiency in PD patient human fibroblasts, by increasing mitochondrial membrane potential and reducing proton leakage.ConclusionsNitrite administration might constitute an amenable neuroprotective strategy in PD. We provide evidence that nitrite mitigates neurodegeneration in PD models and that ameliorates the mitochondrial respiratory profile in primary fibroblasts from genetic PD cases.