Benzimidazole Derivative NS1619 Inhibits Functioning of Mitochondria Isolated from Mouse Skeletal Muscle

IF 1.1 Q4 CELL BIOLOGY
M. V. Dubinin, A. D. Igoshkina, A. A. Semenova, N. V. Mikina, E. I. Khoroshavina, K. N. Belosludtsev
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引用次数: 0

Abstract

The activator of the large-conductance Ca2+-activated K+ channel (BKCa) NS1619 is known to have a pleiotropic action and is able to affect the functioning of other transport systems of the cell and its organelles. In this work, we have studied the effect of this benzimidazole derivative on the functioning of isolated mouse skeletal muscle mitochondria. NS1619 has been shown to dose-dependently inhibit respiration and oxidative phosphorylation of mouse skeletal muscle mitochondria fuelled by glutamate/malate (complex I substrates) or succinate (complex II substrate). This action of NS1619 is based on the inhibition of the activity of complexes I, III, and IV of the respiratory chain of organelles, as well as ATP synthase and is accompanied by a dose-dependent decrease in the membrane potential of organelles fuelled by the above substrates or ATP. In addition, NS1619 significantly reduces the ability of mitochondria to uptake and retain calcium ions in the matrix. At the same time, we noted the antioxidant effect of NS1619 expressed in a decrease in the production of hydrogen peroxide by skeletal muscle mitochondria fuelled by glutamate and malate. The mechanisms of the possible toxic effects of NS1619 on skeletal muscle mitochondrial function and its contribution to the side effects observed in the treatment of muscle pathologies in vivo are discussed.

Abstract Image

苯并咪唑衍生物NS1619对小鼠骨骼肌线粒体功能的抑制作用
已知大电导Ca2+激活K+通道(BKCa) NS1619的激活剂具有多效性,并且能够影响细胞及其细胞器的其他运输系统的功能。在这项工作中,我们研究了这种苯并咪唑衍生物对离体小鼠骨骼肌线粒体功能的影响。NS1619已被证明能够剂量依赖性地抑制由谷氨酸/苹果酸盐(复合物I底物)或琥珀酸盐(复合物II底物)驱动的小鼠骨骼肌线粒体的呼吸和氧化磷酸化。NS1619的这种作用是基于抑制细胞器呼吸链的复合物I、III和IV以及ATP合酶的活性,并伴随着由上述底物或ATP驱动的细胞器膜电位的剂量依赖性降低。此外,NS1619显著降低了线粒体在基质中摄取和保留钙离子的能力。同时,我们注意到NS1619的抗氧化作用表现为减少由谷氨酸和苹果酸驱动的骨骼肌线粒体产生过氧化氢。本文讨论了NS1619对骨骼肌线粒体功能可能的毒性作用机制及其对体内肌肉病理治疗中观察到的副作用的贡献。
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来源期刊
CiteScore
1.40
自引率
0.00%
发文量
28
期刊介绍: Biochemistry (Moscow), Supplement Series A: Membrane and Cell Biology   is an international peer reviewed journal that publishes original articles on physical, chemical, and molecular mechanisms that underlie basic properties of biological membranes and mediate membrane-related cellular functions. The primary topics of the journal are membrane structure, mechanisms of membrane transport, bioenergetics and photobiology, intracellular signaling as well as membrane aspects of cell biology, immunology, and medicine. The journal is multidisciplinary and gives preference to those articles that employ a variety of experimental approaches, basically in biophysics but also in biochemistry, cytology, and molecular biology. The journal publishes articles that strive for unveiling membrane and cellular functions through innovative theoretical models and computer simulations.
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