乙基丙二酸通过以下方式损害生物能学干扰琥珀酸和谷氨酸氧化并诱导大鼠小脑线粒体通透性转换孔开放

Ethylmalonic acid impairs bioenergetics by disturbing succinate and glutamate oxidation

and induces mitochondrial permeability transition pore opening in rat cerebellum

Keywords：bioenergetics; cerebellum; ethylmalonic acid; mitochondrial permeability transition; redox homeostasis

关键词：生物能源学；小脑; 乙基丙二酸；线粒体通透性转变；氧化还原稳态

作者：de Moura Alvorcem Leonardo, Britto Renata, Cecatto Cristiane, Roginski Ana C, Rohden Francieli, Scholl Juliete N, Guma Fatima CR, Figueiro Fabricio, Amaral Alexandre U, Zanatta Geancarlo, Seminotti Bianca, Wajner Moacir, Leipnitz Guilhian
出版期刊：《J Neurochem》(2021)

Abstract：

Tissue accumulation and high urinary excretion of ethylmalonic acid (EMA) are found in ethylmalonic encephalopathy (EE), an inherited disorder associated with cerebral and cerebellar atrophy whose pathogenesis is poorly established. The in vitro and in vivo effects of EMA on bioenergetics and redox homeostasis were investigated in rat cerebellum. For the in vitro studies, cerebellum preparations were exposed to EMA, whereas intracerebellar injection of EMA was used for the in vivo evaluation. EMA reduced state 3 and uncoupled respiration in vitro in succinate-, glutamate-, and malate-supported mitochondria, whereas decreased state 4 respiration was observed using glutamate and malate. Furthermore, mitochondria permeabilization and succinate supplementation diminished the decrease in state 3 with succinate. EMA also inhibited the activity of KGDH, an enzyme necessary for glutamate oxidation, in a mixed manner and augmented mitochondrial efflux of α-ketoglutarate. ATP levels were markedly reduced by EMA, reflecting a severe bioenergetic disruption. Docking simulations also indicated interactions between EMA and KGDH and a competition with glutamate and succinate for their mitochondrial transporters. In vitro findings also showed that EMA decreased mitochondrial membrane potential and Ca2+ retention capacity, and induced swelling in the presence of Ca2+, which were prevented by cyclosporine A and ADP and ruthenium red, indicating mitochondrial permeability transition (MPT). Moreover, EMA, at high concentrations, mildly increased ROS levels and altered antioxidant defenses in vitro and in vivo. Our data indicate that EMA-induced impairment of glutamate and succinate oxidation and MPT may contribute to the pathogenesis of the cerebellum abnormalities in EE.

文章摘要：

乙基丙二酸脑病 (EE) 是一种与脑和小脑萎缩相关的遗传性疾病，其发病机制尚不明确。在大鼠小脑中研究了 EMA 对生物能量学和氧化还原稳态的体外和体内影响。对于体外研究，小脑制剂暴露于 EMA，而小脑内注射 EMA 用于体内评估。 EMA 在琥珀酸、谷氨酸和苹果酸支持的线粒体中降低了状态 3 和体外解偶联呼吸，而使用谷氨酸和苹果酸观察到状态 4 呼吸降低。此外，线粒体通透性和琥珀酸补充减少了状态 3 与琥珀酸的下降。 EMA 还以混合方式抑制 KGDH（一种谷氨酸氧化所必需的酶）的活性，并增加 α-酮戊二酸的线粒体外流。 EMA 显着降低了 ATP 水平，反映了严重的生物能量破坏。对接模拟还表明 EMA 和 KGDH 之间的相互作用以及与谷氨酸和琥珀酸盐的线粒体转运蛋白的竞争。体外研究结果还表明，EMA 降低了线粒体膜电位和 Ca2+ 保留能力，并在 Ca2+ 存在下诱导肿胀，环孢素 A 和 ADP 和钌红可以防止这种情况发生，表明线粒体通透性转变 (MPT)。此外，高浓度的 EMA 在体外和体内轻度增加 ROS 水平并改变抗氧化防御。我们的数据表明 EMA 诱导的谷氨酸和琥珀酸氧化损伤和 MPT 可能有助于 EE 小脑异常的发病机制。

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