Vitamin C in the prevention of cellular respiration (CcO) inhibition by sulfide
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Modulation of sulfide oxidation and toxicity in rat mitochondria by dehydroascorbic acid
"As isolated cytochrome c oxidase activity is strongly inhibited by sulfide at concentrations lower than 1 μM, this aspect has to be considered physiologically relevant even under healthy conditions [20]. Interestingly, respiration of isolated mitochondria or whole cells is significantly less susceptible and not affected by sulfide concentrations up to 5–20 μM [19,21, this study]. At least partially this discrepancy can be explained by an efficient detoxification of the sulfide by the mitochondrial oxidation pathway, which rapidly lowers the ambient concentration. Moreover, other cellular factors might be present in vivo to control the binding of sulfide to cytochrome c oxidase."
"Dehydroascorbic acid is a good candidate for such modifying factor because it has been shown to affect sulfide oxidation in the sulfide adapted invertebrate Arenicola marina [9], and it is readily available in mammalian mitochondria. Ascorbic acid, the main form of vitamin c in cells, functions as a reductant during the biosynthesis of collagen, carnitine and catecholamine thereby producing DHA [22]. Rat and mouse liver contains about 3 mM ascorbic acid [23,24], but it is difficult to determine the physiological DHA concentration because it is rapidly recycled to ascorbic acid by enzymatic and non-enzymatic reduction. A fraction of 5–7 % DHA has been estimated for plasma [25]. However, DHA concentrations can be markedly increased under certain conditions involving oxidative stress such as inflammation or ischemia reperfusion injury [22]. Especially in mitochondria local gradients might occur with a transient increase of DHA in regions of high ROS production at the respiratory chain, where ascorbic acid acts as a major antioxidant. Furthermore, ascorbic acid transport into mitochondria mainly takes place in form of DHA via the glucose transporter GLUT1 [26]."
"The results presented here demonstrate that DHA is able to completely prevent inhibition of cytochrome c oxidase at low sulfide concentrations, which are certainly relevant for mitochondria in the physiological context. As a consequence, mitochondria maintain their regular energy metabolism including ATP production in the presence of this potent inhibitor of the respiratory chain. Partial protection is provided even at relatively high sulfide concentrations that might occur locally or temporarily."
"The easiest explanation for the decrease of sulfide toxicity in the presence of DHA would be a direct interaction of the two compounds. Very high concentrations of sulfide, i.e. a solution saturated with H2S gas, can be used as a reductant to quantitatively convert DHA to ascorbate [27]. Rates of non-enzymatic sulfide consumption also increased after the addition of DHA under the experimental conditions used in this study. Therefore, a decrease of the free sulfide concentration by binding to DHA and chemical oxidation is certainly part of the story. But it is not sufficient to explain all results. If the effect was exclusively chemical it could be expected to be independent of the assay system used to determine cytochrome c oxidase activity. Nevertheless respiration with different substrates such as succinate, NADH and TMPD continued in the presence of 50 μM sulfide plus 1 mM DHA whereas the oxidation of externally added cytochrome c was already completely inhibited at lower sulfide concentrations. Therefore, an additional mechanism probably exists that prevents binding of sulfide to cytochrome c oxidase either by decreasing the affinity or via steric protection of the active site of the enzyme. This effect is independent of membrane potential, as it was not abolished by freezing and thawing of the mitochondria (data not shown)."
"Obviously the rapid oxidation to non-toxic compounds is important for an efficient detoxification of exogenous as well as endogenous sulfide. Especially in the liver this pathway is involved in the degradation of the sulfur containing amino acids methionine and cysteine [42]. DHA also decreases sulfide toxicity in mitochondria from other tissues that have been shown to oxidize sulfide enzymatically such as kidney and heart [19]. As a consequence, sulfide can be used as an inorganic substrate for ATP production in a wide concentration range, but this aspect is presumably of limited importance compared to the normal organic substrates. In contrast to most tissues, brain mitochondria probably lack at least part of the sulfide oxidizing pathway and are therefore more sensitive to sulfide poisoning [19]. The present data support this finding as even in the presence of DHA no enzymatic sulfide oxidation was detectable. However, the protective effect of DHA was most pronounced in the brain demonstrating that this mechanism is particularly important in the absence of an efficient sulfide detoxification pathway."
"The identification of DHA as an instrument to reduce sulfide toxicity may become clinically relevant during the treatment of sulfide poisoning either after accidental environmental exposure or in patients that accumulate endogenous sulfide, e.g. in ethylmalonic encephalopathy. This directed amplification of sulfide oxidation rates could be an alternative therapeutic approach to the inhibition of sulfide producing enzymes, which is already being tested [44]. Maximal intracellular concentrations of vitamin C (3–4 mM) are achieved by supplementation of 200 mg ascorbic acid per day [45]. For acute treatment it is also possible to administer DHA directly via intravenous injection, which raises intracellular ascorbate concentrations to supraphysiological levels and thus probably provides enough DHA to be protective against sulfide toxicity [46]."
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@Amazoniac said in Vitamin C in the prevention of cellular respiration (CcO) inhibition by sulfide:
200 mg ascorbic acid per day
Practical application: that's roughly the amount in 500ml of orange juice, less if it's fresh.
