Bonke Erik, Siebels Ilka, Zwicker Klaus, Dröse Stefan
Department of Anesthesiology, Intensive-Care Medicine and Pain Therapy, University Hospital Frankfurt, 60590 Frankfurt am Main, Germany.
Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt am Main, Germany.
Free Radic Biol Med. 2016 Oct;99:43-53. doi: 10.1016/j.freeradbiomed.2016.07.026. Epub 2016 Jul 26.
Manganese-induced toxicity has been linked to mitochondrial dysfunction and an increased generation of reactive oxygen species (ROS). We could recently show in mechanistic studies that Mn ions induce hydrogen peroxide (HO) production from the ubiquinone binding site of mitochondrial complex II (II) and generally enhance HO formation by accelerating the rate of superoxide dismutation. The present study with intact mitochondria reveals that manganese additionally enhances HO emission by inducing mitochondrial permeability transition (mPT). In mitochondria fed by NADH-generating substrates, the combination of Mn and different respiratory chain inhibitors led to a dynamically increasing HOemission which was sensitive to the mPT inhibitor cyclosporine A (CsA) as well as Ru-360, an inhibitor of the mitochondrial calcium uniporter (MCU). Under these conditions, flavin-containing enzymes of the mitochondrial matrix, e.g. the mitochondrial 2-oxoglutaratedehydrogenase (OGDH), were major sources of ROS. With succinate as substrate, Mn stimulated ROS production mainly at complex II, whereby the applied succinate concentration had a marked effect on the tendency for mPT. Also Ca increased the rate of HO emission by mPT, while no direct effect on ROS-production of complex II was observed. The present study reveals a complex scenario through which manganese affects mitochondrial HO emission: stimulating its production from distinct sites (e.g. site II), accelerating superoxide dismutation and enhancing the emission via mPT which also leads to the loss of soluble components of the mitochondrial antioxidant systems and favors the ROS production from flavin-containing oxidoreductases of the Krebs cycle.
锰诱导的毒性与线粒体功能障碍及活性氧（ROS）生成增加有关。我们最近在机理研究中发现，锰离子可从线粒体复合物II（II）的泛醌结合位点诱导过氧化氢（HO）生成，并通过加速超氧化物歧化速率普遍增强HO的形成。本项针对完整线粒体的研究表明，锰还可通过诱导线粒体通透性转换（mPT）来增强HO的释放。在用产生NADH的底物供能的线粒体中，锰与不同呼吸链抑制剂的组合导致HO释放动态增加，这对mPT抑制剂环孢素A（CsA）以及线粒体钙单向转运体（MCU）抑制剂Ru-360敏感。在这些条件下，线粒体基质中含黄素的酶，如线粒体2-氧代戊二酸脱氢酶（OGDH），是ROS的主要来源。以琥珀酸为底物时，锰主要在复合物II处刺激ROS生成，所施加的琥珀酸浓度对mPT倾向有显著影响。钙也通过mPT增加HO释放速率，而未观察到对复合物II的ROS生成有直接影响。本研究揭示了锰影响线粒体HO释放的复杂情况：从不同位点（如位点II）刺激其生成，加速超氧化物歧化，并通过mPT增强释放，这也导致线粒体抗氧化系统可溶性成分的丧失，并有利于三羧酸循环中含黄素氧化还原酶产生ROS。
