Sulfite disrupts brain mitochondrial energy homeostasis and induces mitochondrial permeability transition pore opening via thiol group modification

Abstract

Sulfite oxidase (SO) deficiency is biochemically characterized by the accumulation of sulfite, thiosulfate and S-sulfocysteine in tissues and biological fluids of the affected patients. The main clinical symptoms include severe neurological dysfunction and brain abnormalities, whose pathophysiology is still unknown. The present study investigated the in vitro effects of sulfite and thiosulfate on mitochondrial homeostasis in rat brain mitochondria. It was verified that sulfite per se, but not thiosulfate, decreased state 3, CCCP-stimulated state and respiratory control ratio in mitochondria respiring with glutamate plus malate. In line with this, we found that sulfite inhibited the activities of glutamate and malate (MDH) dehydrogenases. In addition, sulfite decreased the activity of a commercial solution of MDH, that was prevented by antioxidants and dithiothreitol. Sulfite also induced mitochondrial swelling and reduced mitochondrial membrane potential, Ca(2+) retention capacity, NAD(P)H pool and cytochrome c immunocontent when Ca(2+) was present in the medium. These alterations were prevented by ruthenium red, cyclosporine A (CsA) and ADP, supporting the involvement of mitochondrial permeability transition (MPT) in these effects. We further observed that N-ethylmaleimide prevented the sulfite-elicited swelling and that sulfite decreased free thiol group content in brain mitochondria. These findings indicate that sulfite acts directly on MPT pore containing thiol groups. Finally, we verified that sulfite reduced cell viability in cerebral cortex slices and that this effect was prevented by CsA. Therefore, it may be presumed that disturbance of mitochondrial energy homeostasis and MPT induced by sulfite could be involved in the neuronal damage characteristic of SO deficiency.

Isolated Sulfite Oxidase Deficiency: Response to Dietary Treatment in a Patient with Severe Neonatal Presentation

“…There are several proposed mechanisms by which elevated sulfite leads to neurotoxicity and clinical symptoms 2 . In vitro studies implicate sulfite accumulation in oxidative stress, disturbances of brain mitochondrial energy homeostasis and mitochondrial permeability transition pore opening resulting in neuronal damage characteristic of ISOD 12,13 . Lens dislocation is speculated to occur as a result of reduced levels of cystine (weakening the zonule of the lens) or secondary to elevated sulfites (causing disruption of cysteine disulphide bonds) 4 .…”

Sulfite Oxidase Activity of Cytochrome C: Role of Hydrogen Peroxide

“…In cases of SO deficiency and molybdenum cofactor deficiency, the levels of sulfite and sulfo derivatives of amino acids, proteins, and various compounds are increased in urine [21,24]. SO deficiency also results in the accumulation of sulfite in various tissues, especially in the brain [81]. However, the molecular mechanisms involved are not fully understood.…”

“…It has also been suggested that excess sulfite might damage mitochondrial function via disruption of membrane integrity [9,84]. In rat brain, mitochondrial sulfite induced a decrease in ATP synthesis and disturbance of mitochondrial energy homeostasis [9,81]. In neurons and human fetal liver cells, it has also been shown that ATP is depleted due to sulfite toxicity [9].…”

Integrated Analyses of Microbiome and Longitudinal Metabolome Data Reveal Microbial-Host Interactions on Sulfur Metabolism in Parkinson's Disease

“…Accordingly, B. wadsworthia has been associated with gut inflammation in various mice models with implications for the host sulfur metabolism (Devkota et al, 2012;Natividad et al, 2018). Moreover, sulfite is a known neurotoxin affecting brain mitochondrial energy homeostasis (Grings et al, 2014), and its increase reduces brain cell glutathione levels (Zhang et al, 2004). Accordingly, we observed reduced blood glutathione levels in the follow-ups of the PD patients ( Figure 2B).…”