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Sulfite disrupts brain mitochondrial energy homeostasis and induces mitochondrial permeability transition pore opening via thiol group modification.
- Source :
-
Biochimica et biophysica acta [Biochim Biophys Acta] 2014 Sep; Vol. 1842 (9), pp. 1413-22. Date of Electronic Publication: 2014 May 02. - Publication Year :
- 2014
-
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.<br /> (Copyright © 2014 Elsevier B.V. All rights reserved.)
- Subjects :
- Amino Acid Metabolism, Inborn Errors metabolism
Amino Acid Metabolism, Inborn Errors pathology
Animals
Brain metabolism
Cell Proliferation
Cytochromes c metabolism
Immunoblotting
Male
Membrane Potential, Mitochondrial drug effects
Mitochondria metabolism
Mitochondria, Liver drug effects
Mitochondria, Liver metabolism
Mitochondrial Membrane Transport Proteins metabolism
Mitochondrial Permeability Transition Pore
NADP metabolism
Oxygen Consumption drug effects
Rats
Rats, Wistar
Sulfhydryl Compounds metabolism
Sulfite Oxidase deficiency
Sulfite Oxidase metabolism
Brain drug effects
Energy Metabolism drug effects
Homeostasis drug effects
Mitochondria drug effects
Mitochondrial Membrane Transport Proteins drug effects
Sulfhydryl Compounds chemistry
Sulfites pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 0006-3002
- Volume :
- 1842
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Biochimica et biophysica acta
- Publication Type :
- Academic Journal
- Accession number :
- 24793416
- Full Text :
- https://doi.org/10.1016/j.bbadis.2014.04.022