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L‐OPA1 deficiency aggravates necroptosis of alveolar epithelial cells through impairing mitochondrial function during acute lung injury in mice
Necroptosis, a recently described form of programmed cell death, is the main way of alveolar epithelial cells (AECs) death in acute lung injury (ALI). While the mechanism of how to trigger necroptosis in AECs during ALI has been rarely evaluated. Long optic atrophy protein 1 (L‐OPA1) is a crucial mi...
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Published in: | Journal of cellular physiology 2022-07, Vol.237 (7), p.3030-3043 |
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Main Authors: | , , , , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | Necroptosis, a recently described form of programmed cell death, is the main way of alveolar epithelial cells (AECs) death in acute lung injury (ALI). While the mechanism of how to trigger necroptosis in AECs during ALI has been rarely evaluated. Long optic atrophy protein 1 (L‐OPA1) is a crucial mitochondrial inner membrane fusion protein, and its deficiency impairs mitochondrial function. This study aimed to investigate the role of L‐OPA1 deficiency‐mediated mitochondrial dysfunction in AECs necroptosis. We comprehensively investigated the detailed contribution and molecular mechanism of L‐OPA1 deficiency in AECs necroptosis by inhibiting or activating L‐OPA1. First, our data showed that L‐OPA1 expression was downregulated in the lungs and AECs under the lipopolysaccharide (LPS) challenge. Furthermore, inhibition of L‐OPA1 aggravated the pathological injury, inflammatory response, and necroptosis in the lungs of LPS‐induced ALI mice. In vitro, inhibition of L‐OPA1 induced necroptosis of AECs, while activation of L‐OPA1 alleviated necroptosis of AECs under the LPS challenge. Mechanistically, inhibition of L‐OPA1 aggravated necroptosis of AECs by inducing mitochondrial fragmentation and reducing mitochondrial membrane potential. While activation of L‐OPA1 had the opposite effects. In summary, these findings indicate for the first time that L‐OPA1 deficiency mediates mitochondrial fragmentation, induces necroptosis of AECs, and exacerbates ALI in mice.
L‐OPA1 deficiency mediates mitochondrial fragmentation, induces necroptosis of alveolar epithelial cells, and exacerbates acute lung injury in mice. |
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ISSN: | 0021-9541 1097-4652 |
DOI: | 10.1002/jcp.30766 |