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

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

  • Exp Mol Med. 2022 Nov 28. doi: 10.1038/s12276-022-00889-8.
Hui-Hui Yang 1,  Hui-Ling Jiang 1,  Jia-Hao Tao 1,  Chen-Yu Zhang 1,  Jian-Bing Xiong 1,  Jin-Tong Yang 1,  Yu-Biao Liu 1,  Wen-Jing Zhong 1,  Xin-Xin Guan 1,  Jia-Xi Duan 2,  Yan-Feng Zhang 3,  Shao-Kun Liu 4,  Jian-Xin Jiang 5,  Yong Zhou 6,  Cha-Xiang Guan 7
Affiliations

Affiliations

  • 1 Department of Physiology, School of Basic Medical Science, Central South University, Changsha, Hunan, China.
  • 2 Department of Geriatrics, Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China.
  • 3 Department of Cardiovascular Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.
  • 4 Department of Pulmonary and Critical Care Medicine, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
  • 5 State Key Laboratory of Trauma, Burns, and Combined Injury, Department of Trauma Medical Center, Daping Hospital, Army Medical University, Chongqing, China. hellojjx@126.com.
  • 6 Department of Physiology, School of Basic Medical Science, Central South University, Changsha, Hunan, China. zhouyong421@csu.edu.cn.
  • 7 Department of Physiology, School of Basic Medical Science, Central South University, Changsha, Hunan, China. guanchaxiang@csu.edu.cn.
PMID: 36443565 DOI: 10.1038/s12276-022-00889-8
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 (citratemt) 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 citratemt 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 citratemt levels and rescued AECs from Necroptosis. Mechanistically, citratemt accumulation induced mitochondrial fission and excessive Mitophagy in AECs. Furthermore, citratemt 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 citratemt accumulation was inhibited in FUNDC1-knockout AECs. We show that citratemt accumulation is a novel target for protection against ALI involving Necroptosis.

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