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首页> 外文期刊>Neurochemistry International: The International Journal for the Rapid Publication of Critical Reviews, Preliminary and Original Research Communications in Neurochemistry >Mevalonolactone disrupts mitochondrial functions and induces permeability transition pore opening in rat brain mitochondria: Implications for the pathogenesis of mevalonic aciduria
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Mevalonolactone disrupts mitochondrial functions and induces permeability transition pore opening in rat brain mitochondria: Implications for the pathogenesis of mevalonic aciduria

机译：Mevalonolacterone破坏线粒体功能，并诱导大鼠脑线粒体中的渗透性过渡孔隙开口：对甲戊脲发病机制的影响

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Mevalonic aciduria (MVA) is caused by severe deficiency of mevalonic kinase activity leading to tissue accumulation and high urinary excretion of mevalonic acid (MA) and mevalonolactone (ML). Patients usually present severe neurologic symptoms whose pathophysiology is poorly known. Here, we tested the hypothesis that the major accumulating metabolites are toxic by investigating the in vitro effects of MA and ML on important mitochondrial functions in rat brain and liver mitochondria. ML, but not MA, markedly decreased mitochondrial membrane potential (Delta Psi m), NAD(P)H content and the capacity to retain Ca2+ in the brain, besides inducing mitochondrial swelling. These biochemical alterations were totally prevented by the classical inhibitors of mitochondrial permeability transition (MPT) cyclosporine A and ADP, as well as by ruthenium red in Ca2+-loaded mitochondria, indicating the involvement of MPT and an important role for mitochondrial Ca2+ in these effects. ML also induced lipid peroxidation and markedly inhibited aconitase activity, an enzyme that is highly susceptible to free radical attack, in brain mitochondrial fractions, indicating that lipid and protein oxidative damage may underlie some of ML-induced deleterious effects including MTP induction. In contrast, ML and MA did not compromise oxidative phosphorylation in the brain and all mitochondrial functions evaluated in the liver, evidencing a selective toxicity of ML towards the central nervous system. Our present study provides for the first time evidence that ML impairs essential brain mitochondrial functions with the involvement of MPT pore opening. It is therefore presumed that disturbance of brain mitochondrial homeostasis possibly contributes to the neurologic symptoms in MVA. (C) 2017 Elsevier Ltd. All rights reserved.
机译：麦六醛症（MVA）是由甲瓦次糖激酶活性的严重缺乏引起的，导致组织积累和甲戊酸（MA）和甲卤代酮（mL）的高尿排泄。患者通常表现出严重的神经系统症状，其病理生理学已知不知名。在这里，我们通过研究MA和ML对大鼠脑和肝线粒体中的重要线粒体功能的体外效应来测试主要积累代谢物是毒性的假设。除了诱导线粒体肿胀之外，mL，但不是MA，显着降低线粒体膜电位（Delta PSI M），NAD（P）H含量和保持CA2 +的能力。这些生物化学改变是由线粒体渗透率转变（MPT）环孢菌A和ADP的经典抑制剂，以及Ca2 + -Load的线粒体中的钌红色，表明MPT参与这些作用中的线粒体Ca2 +的重要作用。 ML还诱导脂质过氧化并显着抑制抗肌糖苷酶活性，一种高度易受自由基攻击的酶，脑线粒体分数中的酶，表明脂质和蛋白质氧化损伤可能提出包括MTP诱导的ML诱导的有害作用。相比之下，ml和ma在脑中没有损害脑内的氧化磷酸化和肝脏中的所有线粒体功能，证明了迄今为止ML的选择性毒性。我们现在的研究提供了第一次证据表明ML损害必要的脑线粒体功能与MPT孔隙开口的参与。因此，假设脑线粒体稳态的干扰可能有助于MVA中的神经症状。 （c）2017 Elsevier Ltd.保留所有权利。

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