Intracerebral Administration of Hydrogen Sulfide Impairs Bioenergetics, Redox Status and Mitochondrial Quality...

Elevated hydrogen sulfide (sulfide) levels are observed in tissues, including the brain, of patients with ethylmalonic encephalopathy. Clinical manifestations of this disorder involve severe neurological symptoms and abnormalities such as developmental delay, pyramidal and extrapyramidal signs, cortical atrophy and basal ganglia lesions. To elucidate the pathophysiology of basal ganglia alterations, we investigated the effects of sulfide on bioenergetics, redox status and mitochondrial quality control in the striatum of Wistar rats. After placing the rat in a stereotaxic apparatus, a single intrastriatal administration of sulfide (NaHS; 2 or 4 µmol) or PBS (control) was performed. Thirty minutes after the administration, the rats were euthanized, and the striatum was used for the determination of biochemical parameters. Sulfide administration, at both doses, altered the activities of antioxidant enzymes. At the lowest dose, sulfide showed a strong tendency toward increased activity of citrate synthase. Furthermore, the highest dose of sulfide also reduced respiratory chain complex IV activity and mitochondrial respiration with NADH- and FADH₂-linked substrates. Levels of Nrf2, the main factor that regulates the expression of antioxidant defenses, were also reduced by 4 µmol of sulfide. The metabolite further increased the content of MFN1, suggesting mitochondrial fusion. Additionally, sulfide elevated Parkin and TBC1D15 and reduced LC3 levels, indicative of mitophagy dysregulation. The content of markers of mitochondrial mass and fission were not changed. Our study shows that high levels of sulfide in the striatum of rats affect bioenergetics, redox status and mitochondrial quality control. We suggest that these pathomechanisms are involved in the pathophysiology of basal ganglia alterations verified in ethylmalonic encephalopathy.