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

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 Idh3 alpha and citrate carrier (CIC, also known as Slc25a1). shRNA- or inhibitor-mediated inhibition of Idh3 alpha and Slc25a1 induced citrate(mt) accumulation and necroptosis in vitro. Mice with AEC-specific Idh3 alpha and Slc25a1 deficiency exhibited exacerbated lung injury and AEC necroptosis. Interestingly, the overexpression of Idh3 alpha 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. Acute Lung injury: Citrate as a culprit The process of inflammation-induced cell death, necroptosis, in acute lung injury can be driven by the excessive accumulation of the small biomolecule citrate (a key intermediate of the tricarboxylic acid (TCA) cycle) inside the energy-processing parts of cells called mitochondria. Hui-Hui Yang in Central South University, Hunan, China, and colleagues uncovered this previously unknown mechanism for necroptosis in mouse lung cells exposed to lipopolysaccharide molecules in order to model acute lung injury. They described details of the molecular interactions that allow citrate to damage mitochondria and initiate cell death. They identified a molecular mechanism that could reduce the accumulation of citrate and protect the lung cells from necroptosis. The results suggest that drug treatments to reduce citrate accumulation could offer a novel route to protecting against forms of acute lung injury that involve necroptosis.

Automated summary

The excessive accumulation of citrate in mitochondria can lead to necroptosis, a type of cell death, in acute lung injury. By regulating the expression of certain proteins, the accumulation of citrate can be reduced, thus protecting lung cells from necroptosis.