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Bouillaud 2012 Abstract Bioblast

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Bouillaud F (2012) Coming from the dark ages of mitochondria: sulfide a deadly snare, the best redox food and a signal. Mitochondr Physiol Network 17.12.

Link: MiPNet17.12 Bioblast 2012 - Open Access

Bouillaud F (2012)

Event: Bioblast 2012

Sulfide (H2S gaz HS- anion) shows the same toxicity as cyanide, NO or CO for mitochondrial complex IV (cytochrome oxidase). NO, CO and H2S are considered as gazotransmitters of physiological relevance. While signaling is expected to occur by different pathways, the question of involvement of mitochondria remains sometimes unresolved and particularly because some experiments used « bioenergetically competent » concentrations. Cellular metabolism generates low amount of sulfide and the activity of bacteria in the colonic lumen expose the colonic wall to extracellular concentrations of sulfide (#60µM), large enough to inhibit cellular respiration. Therefore, the question of sulfide disposal needs to be adressed.

Mitochondria themselves appear as best candidate to explain sulfide disposal: a « Sulfide Oxidation Unit » (SOU) oxidizes sulfide into thiosulfate in many cell types in culture and in mitochondria from liver, heart or kidney. When sulfide is infused to mitochondria or cells at rates that stay within their sulfide oxidation capacities they oxidize it and maintain a low (<500nM with cells) external concentration of sulfide well behind the toxic level (IC50 10-20µM with cells). Notably, SOU activity could not be detected in brain mitochondria or neuroblastoma cells making them intolerant to sulfide. SOU is constituted by a sulfide quinone reductase (SQR) associated with a sulfur transferase and a dioxygenase. Present knowledge indicates that two molecules of H2S and one of oxygen (O2) are consumed by SOU to deliver two electrons to quinone. Then the stoichiometry for mitochondrial respiration based on sulfide oxidation is (1+0.5) O2 / 2 H2S = 0.75 and for the same rate of electron transfer three times more oxygen are needed than with NADH/FADH2 coenzymes. In consequence, infusing sulfide immediately and significantly increases oxygen consumption of respiring cells.

Mitochondria show a high affinity for sulfide and its oxidation usually takes priority over ongoing mitochondrial oxidation processes. Something that is mandatory to ensure efficient sulfide disposal in presence of largely greater intracellular concentrations of other substrates. Extracellular sulfide is therefore a remarkable substrate: it could be used at nanomolar concentrations, its gazeous nature allows fast transfer to mitochondria without transporters, it is directly usable to reduce quinone without metabolic processing (including for example initial ATP consuming steps).

This metabolic role of sulfide and its reductant properties contrast sharply with the other two gazotransmitters and particularly with NO which is pro-oxidant. There are still uncertainties about the lowest concentration of sulfide that SQR would « detect » but, in physiological conditions, the overlap between « bioenergetically competent » and signaling concentrations appears even more likely with sulfide than with NO or CO.

Colonocytes are adapted to high sulfide exposure. In these cells « reverse bioenergetic reactions » including reverse electron flux in complex I are taking place to ensure continuation of a fast sulfide oxidation even if complex IV is inhibited.


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