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Restoring mitochondrial cardiolipin homeostasis reduces cell death and promotes recovery after spinal cord injury.


ABSTRACT: Alterations in phospholipids have long been associated with spinal cord injury (SCI). However, their specific roles and signaling cascades in mediating cell death and tissue repair remain unclear. Here we investigated whether alterations of cardiolipin (CL), a family of mitochondrion-specific phospholipids, play a crucial role in mitochondrial dysfunction and neuronal death following SCI. Lipidomic analysis was used to determine the profile of CL alteration in the adult rat spinal cord following a moderate contusive SCI at the 10th thoracic (T10) level. Cellular, molecular, and genetic assessments were performed to determine whether CL alterations mediate mitochondrial dysfunction and neuronal death after SCI, and, if so, whether reversing CL alteration leads to neuroprotection after SCI. Using lipidomic analysis, we uncovered CL alterations at an early stage of SCI. Over 50 distinct CL species were identified, of which 50% showed significantly decreased abundance after SCI. The decreased CL species contained mainly polyunsaturated fatty acids that are highly susceptible to peroxidation. In parallel, 4-HNE, a lipid peroxidation marker, significantly increased after SCI. We found that mitochondrial oxidative stress not only induced CL oxidation, but also resulted in CL loss by activating cPLA2 to hydrolyze CL. CL alterations induced mitochondrial dysfunction and neuronal death. Remarkably, pharmacologic inhibition of CL alterations with XJB-5-131, a novel mitochondria-targeted electron and reactive oxygen species scavenger, reduced cell death, tissue damage and ameliorated motor deficits after SCI in adult rats. These findings suggest that CL alteration could be a novel mechanism that mediates injury-induced neuronal death, and a potential therapeutic target for ameliorating secondary SCI.

SUBMITTER: Liu NK 

PROVIDER: S-EPMC9768173 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Restoring mitochondrial cardiolipin homeostasis reduces cell death and promotes recovery after spinal cord injury.

Liu Nai-Kui NK   Deng Ling-Xiao LX   Wang Miao M   Lu Qing-Bo QB   Wang Chunyan C   Wu Xiangbing X   Wu Wei W   Wang Ying Y   Qu Wenrui W   Han Qi Q   Xia Yongzhi Y   Ravenscraft Baylen B   Li Jin-Lian JL   You Si-Wei SW   Wipf Peter P   Han Xianlin X   Xu Xiao-Ming XM  

Cell death & disease 20221220 12


Alterations in phospholipids have long been associated with spinal cord injury (SCI). However, their specific roles and signaling cascades in mediating cell death and tissue repair remain unclear. Here we investigated whether alterations of cardiolipin (CL), a family of mitochondrion-specific phospholipids, play a crucial role in mitochondrial dysfunction and neuronal death following SCI. Lipidomic analysis was used to determine the profile of CL alteration in the adult rat spinal cord following  ...[more]

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