Mitochondrial Calcium Uniporter (MCU) is Involved in an Ischemic Postconditioning Effect Against Ischemic Reperfusion Brain Injury in Mice

IF 3.6 4区 医学 Q3 CELL BIOLOGY Cellular and Molecular Neurobiology Pub Date : 2024-04-03 DOI:10.1007/s10571-024-01464-7
Hiromitsu Sasaki, Ichiro Nakagawa, Takanori Furuta, Shohei Yokoyama, Yudai Morisaki, Yasuhiko Saito, Hiroyuki Nakase
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Abstract

The phenomenon of ischemic postconditioning (PostC) is known to be neuroprotective against ischemic reperfusion (I/R) injury. One of the key processes in PostC is the opening of the mitochondrial ATP-dependent potassium (mito-KATP) channel and depolarization of the mitochondrial membrane, triggering the release of calcium ions from mitochondria through low-conductance opening of the mitochondrial permeability transition pore. Mitochondrial calcium uniporter (MCU) is known as a highly sensitive transporter for the uptake of Ca2+ present on the inner mitochondrial membrane. The MCU has attracted attention as a new target for treatment in diseases, such as neurodegenerative diseases, cancer, and ischemic stroke. We considered that the MCU may be involved in PostC and trigger its mechanisms. This research used the whole-cell patch-clamp technique on hippocampal CA1 pyramidal cells from C57BL mice and measured changes in spontaneous excitatory post-synaptic currents (sEPSCs), intracellular Ca2+ concentration, mitochondrial membrane potential, and N-methyl-d-aspartate receptor (NMDAR) currents under inhibition of MCU by ruthenium red 265 (Ru265) in PostC. Inhibition of MCU increased the occurrence of sEPSCs (p = 0.014), NMDAR currents (p < 0.001), intracellular Ca2+ concentration (p < 0.001), and dead cells (p < 0.001) significantly after reperfusion, reflecting removal of the neuroprotective effects in PostC. Moreover, mitochondrial depolarization in PostC with Ru265 was weakened, compared to PostC (p = 0.004). These results suggest that MCU affects mitochondrial depolarization in PostC to suppress NMDAR over-activation and prevent elevation of intracellular Ca2+ concentrations against I/R injury.

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线粒体钙离子通道 (MCU) 参与小鼠缺血后条件效应,防止缺血再灌注脑损伤
众所周知,缺血后条件(PostC)现象对缺血再灌注(I/R)损伤具有神经保护作用。PostC 的关键过程之一是线粒体 ATP 依赖性钾(mito-KATP)通道的开放和线粒体膜的去极化,通过线粒体通透性转换孔的低导开放引发钙离子从线粒体释放。线粒体钙离子单向传输器(MCU)是线粒体内膜上一种高度敏感的钙离子吸收传输器。MCU 作为治疗神经退行性疾病、癌症和缺血性中风等疾病的新靶点备受关注。我们认为 MCU 可能参与了 PostC 并触发了其机制。本研究采用全细胞贴片钳技术对C57BL小鼠海马CA1锥体细胞进行了研究,测量了PostC中钌红265(Ru265)抑制MCU时自发兴奋性突触后电流(sEPSCs)、细胞内Ca2+浓度、线粒体膜电位和N-甲基-d-天冬氨酸受体(NMDAR)电流的变化。抑制 MCU 会显著增加再灌注后 sEPSCs 的发生(p = 0.014)、NMDAR 电流(p < 0.001)、细胞内 Ca2+ 浓度(p < 0.001)和死亡细胞(p < 0.001),这反映了 PostC 中神经保护作用的消失。此外,与PostC相比,Ru265在PostC中的线粒体去极化作用减弱(p = 0.004)。这些结果表明,MCU会影响PostC中线粒体的去极化,从而抑制NMDAR的过度激活,防止细胞内Ca2+浓度升高,减轻I/R损伤。
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来源期刊
CiteScore
7.70
自引率
0.00%
发文量
137
审稿时长
4-8 weeks
期刊介绍: Cellular and Molecular Neurobiology publishes original research concerned with the analysis of neuronal and brain function at the cellular and subcellular levels. The journal offers timely, peer-reviewed articles that describe anatomic, genetic, physiologic, pharmacologic, and biochemical approaches to the study of neuronal function and the analysis of elementary mechanisms. Studies are presented on isolated mammalian tissues and intact animals, with investigations aimed at the molecular mechanisms or neuronal responses at the level of single cells. Cellular and Molecular Neurobiology also presents studies of the effects of neurons on other organ systems, such as analysis of the electrical or biochemical response to neurotransmitters or neurohormones on smooth muscle or gland cells.
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