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-specif...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2022-12-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-022-05369-5 |
| _version_ | 1828086865669914624 |
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| author | Nai-Kui Liu Ling-Xiao Deng Miao Wang Qing-Bo Lu Chunyan Wang Xiangbing Wu Wei Wu Ying Wang Wenrui Qu Qi Han Yongzhi Xia Baylen Ravenscraft Jin-Lian Li Si-Wei You Peter Wipf Xianlin Han Xiao-Ming Xu |
| author_facet | Nai-Kui Liu Ling-Xiao Deng Miao Wang Qing-Bo Lu Chunyan Wang Xiangbing Wu Wei Wu Ying Wang Wenrui Qu Qi Han Yongzhi Xia Baylen Ravenscraft Jin-Lian Li Si-Wei You Peter Wipf Xianlin Han Xiao-Ming Xu |
| author_sort | Nai-Kui Liu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T05:03:52Z |
| format | Article |
| id | doaj.art-25441a47b06f41fe8fc1e177c855cf32 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-11T05:03:52Z |
| publishDate | 2022-12-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-25441a47b06f41fe8fc1e177c855cf322022-12-25T12:31:53ZengNature Publishing GroupCell Death and Disease2041-48892022-12-01131211610.1038/s41419-022-05369-5Restoring mitochondrial cardiolipin homeostasis reduces cell death and promotes recovery after spinal cord injuryNai-Kui Liu0Ling-Xiao Deng1Miao Wang2Qing-Bo Lu3Chunyan Wang4Xiangbing Wu5Wei Wu6Ying Wang7Wenrui Qu8Qi Han9Yongzhi Xia10Baylen Ravenscraft11Jin-Lian Li12Si-Wei You13Peter Wipf14Xianlin Han15Xiao-Ming Xu16Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Department of Neurological Surgery, Indiana University School of MedicineSpinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Department of Neurological Surgery, Indiana University School of MedicineFrontage LaboratoriesSpinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Department of Neurological Surgery, Indiana University School of MedicineDepartment of Medicine, Washington University School of MedicineSpinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Department of Neurological Surgery, Indiana University School of MedicineSpinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Department of Neurological Surgery, Indiana University School of MedicineSpinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Department of Neurological Surgery, Indiana University School of MedicineSpinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Department of Neurological Surgery, Indiana University School of MedicineSpinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Department of Neurological Surgery, Indiana University School of MedicineSpinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Department of Neurological Surgery, Indiana University School of MedicineSpinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Department of Neurological Surgery, Indiana University School of MedicineDepartment of Anatomy and K.K. Leung Brain Research Centre, Preclinical School of Medicine, The Fourth Military Medical UniversityInstitute of Neuroscience, The Fourth Military Medical UniversityDepartment of Chemistry, University of PittsburghDepartment of Medicine, University of Texas Health Science Center at San AntonioSpinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Department of Neurological Surgery, Indiana University School of MedicineAbstract 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.https://doi.org/10.1038/s41419-022-05369-5 |
| spellingShingle | Nai-Kui Liu Ling-Xiao Deng Miao Wang Qing-Bo Lu Chunyan Wang Xiangbing Wu Wei Wu Ying Wang Wenrui Qu Qi Han Yongzhi Xia Baylen Ravenscraft Jin-Lian Li Si-Wei You Peter Wipf Xianlin Han Xiao-Ming Xu Restoring mitochondrial cardiolipin homeostasis reduces cell death and promotes recovery after spinal cord injury Cell Death and Disease |
| title | Restoring mitochondrial cardiolipin homeostasis reduces cell death and promotes recovery after spinal cord injury |
| title_full | Restoring mitochondrial cardiolipin homeostasis reduces cell death and promotes recovery after spinal cord injury |
| title_fullStr | Restoring mitochondrial cardiolipin homeostasis reduces cell death and promotes recovery after spinal cord injury |
| title_full_unstemmed | Restoring mitochondrial cardiolipin homeostasis reduces cell death and promotes recovery after spinal cord injury |
| title_short | Restoring mitochondrial cardiolipin homeostasis reduces cell death and promotes recovery after spinal cord injury |
| title_sort | restoring mitochondrial cardiolipin homeostasis reduces cell death and promotes recovery after spinal cord injury |
| url | https://doi.org/10.1038/s41419-022-05369-5 |
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