Negative modulation of mitochondrial calcium uniporter complex protects neurons against ferroptosis.
Negative modulation of mitochondrial calcium uniporter complex protects neurons against ferroptosis.
复制标题
负调节线粒体单转运钙复合体保护神经元免受铁下垂。
DOI：
10.1038/s41419-023-06290-1
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发表时间：
2023-11-25
影响因子：
9
通讯作者：
Dolga, Amalia M.
中科院分区：
文献类型：
--
作者：
Marmolejo-Garza, Alejandro;Krabbendam, Inge E.;Luu, Minh Danh Anh;Brouwer, Famke;Trombetta-Lima, Marina;Unal, Osman;O'Connor, Shane J.;Majernikova, Nad'a;Elzinga, Carolina R. S.;Mammucari, Cristina;Schmidt, Martina;Madesh, Muniswamy;Boddeke, Erik;Dolga, Amalia M.
铁死亡是一种铁和活性氧 (ROS) 依赖性的受调节细胞死亡形式，与阿尔茨海默病和帕金森病有关。抑制胱氨酸/谷氨酸逆向转运蛋白可能导致线粒体断裂、线粒体钙 ([Ca2+]m) 超载、线粒体 ROS 产生增加、线粒体膜电位 (ΔΨm) 破坏和铁死亡。线粒体功能障碍是铁死亡的一个特征，这一观察结果使得保留线粒体功能成为铁死亡相关疾病的潜在治疗选择。线粒体钙水平通过线粒体钙单向转运蛋白 (MCU) 控制，它是 Ca2+ 进入线粒体基质的主要入口点。因此，我们假设 MCU 复合体的负调节可能有助于防止铁死亡。在此，我们评估了已知的 MCU 复合物负调节剂、钌红 (RR)、其衍生物 Ru265、米托蒽醌 (MX) 和 MCU-i4 是否可以预防线粒体功能障碍和铁死亡。这些化合物介导 HT22 细胞、人类多巴胺能神经元和小鼠原代皮质神经元的保护，防止铁死亡。 MICU1（[Ca2+]m 看门人）的耗尽表明 MICU 具有预防铁死亡的保护作用。总而言之，我们的结果表明，MCU 复合物的负调节代表了预防退行性疾病的一种治疗选择，其中铁死亡是这些病理进展的核心。
Ferroptosis is an iron- and reactive oxygen species (ROS)-dependent form of regulated cell death, that has been implicated in Alzheimer’s disease and Parkinson’s disease. Inhibition of cystine/glutamate antiporter could lead to mitochondrial fragmentation, mitochondrial calcium ([Ca2+]m) overload, increased mitochondrial ROS production, disruption of the mitochondrial membrane potential (ΔΨm), and ferroptotic cell death. The observation that mitochondrial dysfunction is a characteristic of ferroptosis makes preservation of mitochondrial function a potential therapeutic option for diseases associated with ferroptotic cell death. Mitochondrial calcium levels are controlled via the mitochondrial calcium uniporter (MCU), the main entry point of Ca2+ into the mitochondrial matrix. Therefore, we have hypothesized that negative modulation of MCU complex may confer protection against ferroptosis. Here we evaluated whether the known negative modulators of MCU complex, ruthenium red (RR), its derivative Ru265, mitoxantrone (MX), and MCU-i4 can prevent mitochondrial dysfunction and ferroptotic cell death. These compounds mediated protection in HT22 cells, in human dopaminergic neurons and mouse primary cortical neurons against ferroptotic cell death. Depletion of MICU1, a [Ca2+]m gatekeeper, demonstrated that MICU is protective against ferroptosis. Taken together, our results reveal that negative modulation of MCU complex represents a therapeutic option to prevent degenerative conditions, in which ferroptosis is central to the progression of these pathologies.
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影响因子：
7
作者：
Ito K;Eguchi Y;Imagawa Y;Akai S;Mochizuki H;Tsujimoto Y
通讯作者：
Tsujimoto Y
影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
KCA2通道激活可防止[Ca2+] I失调并减少谷氨酸毒性和脑缺血后神经元死亡。
影响因子：
9
作者：
通讯作者：
--
影响因子：
6.1
作者：
Eleuteri, Simona;Di Giovanni, Saviana;Rockenstein, Edward;Mante, Mike;Adame, Antony;Trejo, Margarita;Wrasidlo, Wolf;Wu, Fang;Fraering, Patrick C.;Masliah, Eliezer;Lashuel, Hilal A.
通讯作者：
Lashuel, Hilal A.
DOI：
10.1016/j.bbamcr.2017.01.015
发表时间：
2017-06
期刊：
Biochimica et biophysica acta. Molecular cell research
影响因子：
--
作者：
Bhosale G;Sharpe JA;Koh A;Kouli A;Szabadkai G;Duchen MR
通讯作者：
Duchen MR