Abnormalities of one carbon, glutathione and sulfide metabolisms have recently emerged as novel pathomechanisms in diseases with mitochondrial dysfunction. However, the mechanisms underlying these abnormalities are not clear. Also, we recently showed that sulfide oxidation is impaired in Coenzyme Q₁₀ (CoQ₁₀) deficiency. This finding leads us to hypothesize that the therapeutic effects of CoQ₁₀, frequently administered to patients with primary or secondary mitochondrial dysfunction, might be due to its function as cofactor for sulfide:quinone oxidoreductase (SQOR), the first enzyme in the sulfide oxidation pathway. Here, using biased and unbiased approaches, we show that supraphysiological levels of CoQ₁₀ induces an increase in the expression of SQOR in skin fibroblasts from control subjects and patients with mutations in Complex I subunits genes or CoQ biosynthetic genes. This increase of SQOR induces the downregulation of the cystathionine β-synthase and cystathionine γ-lyase, two enzymes of the transsulfuration pathway, the subsequent downregulation of serine biosynthesis and the adaptation of other sulfide linked pathways, such as folate cycle, nucleotides metabolism and glutathione system. These metabolic changes are independent of the presence of sulfur aminoacids, are confirmed in mouse models, and are recapitulated by overexpression of SQOR, further proving that the metabolic effects of CoQ₁₀ supplementation are mediated by the overexpression of SQOR. Our results contribute to a better understanding of how sulfide metabolism is integrated in one carbon metabolism and may explain some of the benefits of CoQ₁₀ supplementation observed in mitochondrial diseases.

中文翻译：

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辅酶 Q10 调节硫化物代谢并将线粒体呼吸链与与单碳代谢相关的途径联系起来。

一碳、谷胱甘肽和硫化物代谢异常最近已成为线粒体功能障碍疾病的新病理机制。然而，这些异常背后的机制尚不清楚。此外，我们最近发现辅酶 Q ₁₀ (CoQ ₁₀ ) 缺乏症会损害硫化物氧化。这一发现使我们假设 CoQ ₁₀的治疗效果，经常给予患有原发性或继发性线粒体功能障碍的患者，可能是由于其作为硫化物辅助因子的功能：醌氧化还原酶 (SQOR)，硫化物氧化途径中的第一种酶. 在这里，使用有偏见和无偏见的方法，我们表明 CoQ _{10 的超}生理水平诱导来自对照受试者和复合物 I 亚基基因或 CoQ 生物合成基因突变患者的皮肤成纤维细胞中SQOR的表达增加。SQOR 的增加导致胱硫醚 β-合酶和胱硫醚 γ-裂解酶（转硫途径的两种酶）下调，随后丝氨酸生物合成下调以及其他与硫化物相关的途径（如叶酸循环、核苷酸代谢和谷胱甘肽）的适应系统。这些代谢变化与硫氨基酸的存在无关，在小鼠模型中得到证实，并通过 SQOR 的过表达进行概括，进一步证明 CoQ ₁₀的代谢作用补充是由 SQOR 的过度表达介导的。我们的研究结果有助于更好地了解硫化物代谢如何整合到一碳代谢中，并可能解释在线粒体疾病中观察到的 CoQ ₁₀补充剂的一些好处。