Methylmalonate inhibits succinate-supported oxygen consumption by interfering with mitochondrial succinate uptake.
Methylmalonate inhibits succinate-supported oxygen consumption by interfering with mitochondrial succinate uptake.
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丙二酸甲酯通过干扰线粒体琥珀酸摄取来抑制琥珀酸支持的氧消耗。
DOI：
10.1007/s10545-007-0798-1
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发表时间：
2008
影响因子：
4.2
通讯作者：
Castilho,RF
中科院分区：
文献类型：
--
作者：
Mirandola,SR;Melo,DR;Schuck,PF;Ferreira,GC;Wajner,M;Castilho,RF
甲基丙二酸（MMA）对线粒体琥珀酸氧化的影响因其在甲基丙二酸血症的能量代谢障碍中起重要作用而受到广泛关注。在目前的工作中，我们表明，虽然毫摩尔浓度的MMA抑制琥珀酸支持的氧消耗分离大鼠脑或肌肉线粒体，有没有影响时，无论是池的NADH连接的底物或N，N，N′，N′-四甲基对苯二胺（TMPD）/抗坏血酸被用作电子供体。有趣的是，MMA的抑制作用，但不是丙二酸盐，琥珀酸支持的脑线粒体耗氧量最小化时，非选择性透化的线粒体膜诱导丙甲霉素。此外，只有轻微的抑制作用的MMA琥珀酸支持的氧消耗观察到由内而外的亚线粒体颗粒。与这些观察结果一致，脑线粒体肿胀实验表明，MMA是一个重要的抑制剂琥珀酸转运的二羧酸载体。在我们的实验条件下，没有证据表明丙二酸生产在MMA处理的线粒体。我们的结论是，MMA抑制琥珀酸支持的线粒体耗氧量干扰这种基板的摄取。虽然线粒体外产生的琥珀酸可能不是线粒体能量产生的重要贡献者，但MMA诱导的线粒体二羧酸载体抑制底物转运的生理病理学意义进行了讨论。
The effect of methylmalonate (MMA) on mitochondrial succinate oxidation has received great attention since it could present an important role in energy metabolism impairment in methylmalonic acidaemia. In the present work, we show that while millimolar concentrations of MMA inhibit succinate-supported oxygen consumption by isolated rat brain or muscle mitochondria, there is no effect when either a pool of NADH-linked substrates orN,N,N′,N′-tetramethyl-p-phenylendiamine (TMPD)/ascorbate were used as electron donors. Interestingly, the inhibitory effect of MMA, but not of malonate, on succinate-supported brain mitochondrial oxygen consumption was minimized when nonselective permeabilization of mitochondrial membranes was induced by alamethicin. In addition, only a slight inhibitory effect of MMA was observed on succinate-supported oxygen consumption by inside-out submitochondrial particles. In agreement with these observations, brain mitochondrial swelling experiments indicate that MMA is an important inhibitor of succinate transport by the dicarboxylate carrier. Under our experimental conditions, there was no evidence of malonate production in MMA-treated mitochondria. We conclude that MMA inhibits succinate-supported mitochondrial oxygen consumption by interfering with the uptake of this substrate. Although succinate generated outside the mitochondria is probably not a sig-nificant contributor to mitochondrial energy generation, the physiopathological implications of MMA-induced inhibition of substrate transport by the mitochondrial dicarboxylate carrier are discussed.