期刊
JOURNAL OF CELLULAR PHYSIOLOGY
卷 237, 期 7, 页码 3030-3043出版社
WILEY
DOI: 10.1002/jcp.30766
关键词
acute lung injury; alveolar epithelial cells; L-OPA1; mitochondrial fragmentation; necroptosis
资金
- National Natural Science Foundation of China [91949110, 82170096]
- High School Innovation Fund of Hunan province [19K103]
- Health Commission Fund of Hunan province [202202015410, 202202015492]
- Fundamental Research Funds for the Central Universities of Central South University [2019zzts893]
This study investigated the role of L-OPA1 deficiency-mediated mitochondrial dysfunction in the necroptosis of alveolar epithelial cells (AECs). The findings revealed that inhibition of L-OPA1 aggravated the pathological injury, inflammatory response, and necroptosis in the lungs of LPS-induced acute lung injury mice. In vitro experiments demonstrated that inhibition of L-OPA1 induced necroptosis of AECs, while activation of L-OPA1 alleviated necroptosis of AECs under the LPS challenge.
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.
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