3-羟基-3-甲基戊二酸损害大鼠大脑中的氧化还原和能量稳态、线粒体动力学和内质网-线粒体串扰。,Neurotoxicity Research

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3-羟基-3-甲基戊二酸损害大鼠大脑中的氧化还原和能量稳态、线粒体动力学和内质网-线粒体串扰。
Neurotoxicity Research ( IF 2.9 ) Pub Date : 2019-11-13 , DOI: 10.1007/s12640-019-00122-x
Mateus Struecker da Rosa ₁ , Nevton Teixeira da Rosa-Junior ₁ , Belisa Parmeggiani ₁ , Nícolas Manzke Glänzel ₁ , Leonardo de Moura Alvorcem ₁ , Rafael Teixeira Ribeiro ₁ , Mateus Grings ₁ , Moacir Wajner _{2,

3} , Guilhian Leipnitz _{2,

4}

Affiliation

3-Hydroxy-3-methylglutaryl-CoA 裂解酶 (HL) 缺乏症是一种神经代谢紊乱，其特征是 3-hydroxy-3-methylglutaric acid (HMG) 在组织和生物体液中大量积累。患者通常在出生后的第一年出现代谢性酸中毒、非酮症性低血糖、肌张力减退、嗜睡和昏迷。由于在代谢失代偿期间可能会触发或恶化神经系统症状，其特征是有机酸的高尿排泄，本研究调查了 HMG 脑室内给药对氧化还原稳态、柠檬酸循环酶活性、动力学（线粒体融合和裂变）的影响)，以及注射后 1 天（短期）或 20 天（长期）安乐死的新生大鼠大脑中的内质网 (ER)-线粒体串扰。HMG 诱导脂质过氧化并降低谷胱甘肽过氧化物酶 (GPx) 和柠檬酸循环酶的活性，表明给药后 1 天生物能量和氧化还原破坏。HMG 增加了参与 ER-线粒体串扰和线粒体融合的蛋白质 VDAC1、Grp75 和 mitofusin-1 的水平。此外，HMG 降低突触素水平和 tau 磷酸化，并增加活性 caspase-3 含量，表明细胞受损。最后，HMG 降低了 GPx 活性和突触素水平，并在注射后 20 天改变了 MAPK 磷酸化，表明这种有机酸进一步诱导了长期毒性。总之，这些数据表明 HMG 诱导氧化应激并破坏生物能量学、动力学、ER-线粒体通讯，和出生后不久大鼠大脑中的信号通路。可以推测，这些机制是新生儿期 HL 缺陷患者失代偿期间症状发作和进展的基础。

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3-Hydroxy-3-Methylglutaric Acid Impairs Redox and Energy Homeostasis, Mitochondrial Dynamics, and Endoplasmic Reticulum-Mitochondria Crosstalk in Rat Brain.

3-Hydroxy-3-methylglutaryl-CoA lyase (HL) deficiency is a neurometabolic disorder characterized by predominant accumulation of 3-hydroxy-3-methylglutaric acid (HMG) in tissues and biological fluids. Patients often present in the first year of life with metabolic acidosis, non-ketotic hypoglycemia, hypotonia, lethargy, and coma. Since neurological symptoms may be triggered or worsened during episodes of metabolic decompensation, which are characterized by high urinary excretion of organic acids, this study investigated the effects of HMG intracerebroventricular administration on redox homeostasis, citric acid cycle enzyme activities, dynamics (mitochondrial fusion and fission), and endoplasmic reticulum (ER)–mitochondria crosstalk in the brain of neonatal rats euthanized 1 (short term) or 20 days (long term) after injection. HMG induced lipid peroxidation and decreased the activities of glutathione peroxidase (GPx) and citric acid cycle enzymes, suggesting bioenergetic and redox disruption, 1 day after administration. Levels of VDAC1, Grp75, and mitofusin-1, proteins involved in ER-mitochondria crosstalk and mitochondrial fusion, were increased by HMG. Furthermore, HMG diminished synaptophysin levels and tau phosphorylation, and increased active caspase-3 content, indicative of cell damage. Finally, HMG decreased GPx activity and synaptophysin levels, and changed MAPK phosphorylation 20 days after injection, suggesting that long-term toxicity is further induced by this organic acid. Taken together, these data show that HMG induces oxidative stress and disrupts bioenergetics, dynamics, ER-mitochondria communication, and signaling pathways in the brain of rats soon after birth. It may be presumed that these mechanisms underlie the onset and progression of symptoms during decompensation occurring in HL-deficient patients during the neonatal period.

更新日期：2019-11-13

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