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Mitochondrial citrate accumulation drives alveolar epithelial cell necroptosis in lipopolysaccharide-induced acute lung injury.

ABSTRACT: Necroptosis is the major cause of death in alveolar epithelial cells (AECs) during acute lung injury (ALI). Here, we report a previously unrecognized mechanism for necroptosis. We found an accumulation of mitochondrial citrate (citrate^mt) in lipopolysaccharide (LPS)-treated AECs because of the downregulation of Idh3α and citrate carrier (CIC, also known as Slc25a1). shRNA- or inhibitor-mediated inhibition of Idh3α and Slc25a1 induced citrate^mt accumulation and necroptosis in vitro. Mice with AEC-specific Idh3α and Slc25a1 deficiency exhibited exacerbated lung injury and AEC necroptosis. Interestingly, the overexpression of Idh3α and Slc25a1 decreased citrate^mt levels and rescued AECs from necroptosis. Mechanistically, citrate^mt accumulation induced mitochondrial fission and excessive mitophagy in AECs. Furthermore, citrate^mt directly interacted with FUN14 domain-containing protein 1 (FUNDC1) and promoted the interaction of FUNDC1 with dynamin-related protein 1 (DRP1), leading to excessive mitophagy-mediated necroptosis and thereby initiating and promoting ALI. Importantly, necroptosis induced by citrate^mt accumulation was inhibited in FUNDC1-knockout AECs. We show that citrate^mt accumulation is a novel target for protection against ALI involving necroptosis.

SUBMITTER: Yang HH

PROVIDER: S-EPMC9722936 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Mitochondrial citrate accumulation drives alveolar epithelial cell necroptosis in lipopolysaccharide-induced acute lung injury.

Yang Hui-Hui HH Jiang Hui-Ling HL Tao Jia-Hao JH Zhang Chen-Yu CY Xiong Jian-Bing JB Yang Jin-Tong JT Liu Yu-Biao YB Zhong Wen-Jing WJ Guan Xin-Xin XX Duan Jia-Xi JX Zhang Yan-Feng YF Liu Shao-Kun SK Jiang Jian-Xin JX Zhou Yong Y Guan Cha-Xiang CX

Experimental & molecular medicine 20221128 11

Necroptosis is the major cause of death in alveolar epithelial cells (AECs) during acute lung injury (ALI). Here, we report a previously unrecognized mechanism for necroptosis. We found an accumulation of mitochondrial citrate (citrate<sup>mt</sup>) in lipopolysaccharide (LPS)-treated AECs because of the downregulation of Idh3α and citrate carrier (CIC, also known as Slc25a1). shRNA- or inhibitor-mediated inhibition of Idh3α and Slc25a1 induced citrate<sup>mt</sup> accumulation and necroptosis i ...[more]

PMID: 36443565

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Project description:Background: B-cell receptor-associated protein 31 (BCAP31) has protective effects against alveolar epithelial type II cells (AECII) damage by inhibiting mitochondrial injury in acute lung injury (ALI) induced by lipopolysaccharide (LPS), whereas the precise mechanism is still unclear. It is known that PTEN-induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy can remove damaged mitochondria selectively, which may be involved in BCAP31 protection against mitochondrial injury. Methods: In the current study, ALI mice models were established by using surfactant protein C (Sftpc)-BCAP31 transgenic mice (BCAP31TG mice) and AECII-specific BCAP31 knockout mice (BCAP31CKO mice) treated with LPS. Results: BCAP31 expression in lung tissue and AECII were inhibited in ALI mice. Under LPS challenge, lower level of BCAP31 was found to correlate positively with pathological injury of the lung, respiratory dysfunction, mortality rates, inflammation response, and AECII damage. Further study showed that down-regulation of BCAP31 induced decreased phosphorylation of PINK1 via reduced binding to PINK1, thereby restraining PINK1/Parkin-mediated mitophagy. Down-regulation of mitophagy promoted mitochondrial injury, as shown by the increase in mitochondrial permeability transition pore opening rate, together with enhanced mitochondrial reactive oxygen species (mROS), which were accompanied by increased cellular apoptosis and reactive oxygen species (ROS). The increased cellular ROS contributed to the inflammatory response via activation of nuclear factor κB (NF-κB). In contrast, BCAP31 overexpression promoted phosphorylation of PINK1 and PINK1/Parkin-mediated mitophagy, thus blocking the mROS/ROS/NF-κB pathway, favoring a protective condition that ultimately led to the inhibition of AECII apoptosis and inflammatory response in LPS-induced ALI. Conclusion: Ultimately, BCAP31 alleviated ALI by activating PINK1/Parkin-mediated mitophagy and blocking the mROS/ROS/NF-κB pathway in AECII.

Dataset Information

Mitochondrial citrate accumulation drives alveolar epithelial cell necroptosis in lipopolysaccharide-induced acute lung injury.

Publications

Mitochondrial citrate accumulation drives alveolar epithelial cell necroptosis in lipopolysaccharide-induced acute lung injury.

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