Uniporter公司
细胞生物学
钙
线粒体
钙信号传导
生物
化学
生物物理学
神经科学
信号转导
生物化学
酶
胞浆
有机化学
作者
Alejandro Marmolejo-Garza,Inge Krabbendam,Mai Luu,Famke Brouwer,Marina Trombetta-Lima,Özlem Ünal,Shane J. O’Connor,Nad’a Majerníková,Carolina Elzinga,Cristina Mammucari,Martina Schmidt,Muniswamy Madesh,Erik Boddeke,Amalia M. Dolga
标识
DOI:10.1038/s41419-023-06290-1
摘要
Abstract 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 ([Ca 2+ ] m ) overload, increased mitochondrial ROS production, disruption of the mitochondrial membrane potential (ΔΨ m ), 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 Ca 2+ 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 [Ca 2+ ] 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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