Sodium Propionate Protects Dopaminergic Neurons Against Mitochondrial Toxin–Induced Oxidative Stress In Vitro

Identifying a metabolic rescue for mitochondrial toxins induced neurodegeneration is a promising therapeutic target. Dopaminergic neurons are high energy dependent neurons, owing to their metabolic functions, and this makes them vulnerable in conditions of bioenergetic failure and mitochondrial dysfunction. In this study, we explored the protective potential of sodium propionate, a short-chain fatty acid and metabolic precursor of succinate, against mitochondrial toxin-induced neurotoxicity in MN9D dopaminergic cells. Cells were treated with 200 µM sodium propionate after exposure to 1.5 µM rotenone or 10 µM antimycin A, and cell viability, intracellular ATP levels, reactive oxygen species (ROS) generation, and dopaminergic markers were assessed. Our results show that sodium propionate significantly attenuates mitochondrial toxin-induced loss of cell viability and ATP depletion while reducing oxidative stress and preserving the expression of enzymes involved in catecholamine biosynthesis pathway, including tyrosine hydroxylase (TH) and dopamine β-hydroxylase (DBH). These findings suggest that sodium propionate confers functional protection to dopaminergic neurons under mitochondrial toxin stress. Sodium propionate is proposed to act as a metabolic precursor to succinyl-CoA, thereby replenishing tricarboxylic acid cycle intermediates and supporting cellular metabolic homeostasis. Under Complex I inhibition (rotenone) and complex III inhibition (antimycin A), sodium propionate treatment was associated with preservation of cellular ATP levels. Across conditions, sodium propionate treatment was associated with improved cell viability, reduced oxidative stress associated signals, and preservation of dopaminergic function. Together, these data indicate that sodium propionate supports dopaminergic neuronal resilience through toxin-dependent metabolic and cellular stress modulating effects.