Lactylation: a promising therapeutic target in ischemia-reperfusion injury management

Figures

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  Fig. 1. Overview of lactate metabolism. Lactate production and metabolism within cells encompass several key steps: Initially, lactate is translocated across the cellular membrane via the MCT, moving from the extracellular environment into the cytoplasm. Lactate formation occurs either through glycolytic processes or from the breakdown of glutamine. Cellular lactate catabolism is divided into two primary pathways. The first involves the oxidation of lactate to pyruvate, which is then transported into the mitochondria for subsequent catabolism within the TCA cycle. The second pathway involves the conversion of lactate back to glucose via gluconeogenesis. α-KG α-ketoglutaric acid, MCT monocarboxylate transporter, PDH pyruvate dehydrogenase, TCA tricarboxylic acid. Created with Figdraw.

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  Fig. 2. Lactate regulates immune cell behavior to impact inflammation. Lactate plays a significant role in cellular metabolism by inhibiting mitochondrial oxidative phosphorylation, thereby contributing to mitochondrial dysfunction. Moreover, lactate demonstrates the capacity to modulate the activation of immune cells such as T cells, B cells, NK cells, neutrophils, macrophages, and mast cells. This modulation leads to the secretion of specific cytokines, which exert a profound influence on the inflammatory response. Arg1 arginase-1, CXCL CXC motif chemokine, G-CSF granulocyte colony-stimulating factor, GPR81 G-protein-coupled receptor 81, IFN-γ interferon-γ, IFNs type I interferons, IL-17 interleukin-17, NKp46 lysis receptor 46 of natural killer cell, PD-1 programmed cell death protein 1, PD-L1 programmed cell death protein 1 ligand, Th1 type 1 helper T cells, Th17 type 17 helper T cells, Tregs regulatory T cells, VEGF vascular endothelial growth factor. Created with Figdraw.

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  Fig. 3. Simplified schematic representation of ischemia-reperfusion injury. In the context of ischemia-reperfusion injury, there is a reduction in intracellular ATP levels and pH, attributed to anaerobic metabolism and the accumulation of lactate. Consequently, there is a compromise in the ATP-dependent ion transport mechanism. This disruption precipitates intracellular and intra-mitochondrial calcium overload, leading to mitochondrial dysfunction and a subsequent upsurge in the production of inflammatory factors. Additionally, the release of the corresponding cytokines and chemokines induces immune cell infiltration. These biochemical alterations result in cellular swelling, rupture, and demise. Modes of cell death encompass necrosis, apoptosis, pyroptosis, autophagy, and other associated pathways. IL-1β interleukin-1β, ROS reactive oxygen species, TNF-α tumor necrosis factor-α. Created with Figdraw.

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  Fig. 4. Overview of the lactylation mechanism. Lactate transport from extracellular to intracellular compartments, coupled with its generation via glycolysis, facilitates the lactylation of lysine residues on both histone and nonhistone proteins. This modification occurs through either enzyme-dependent or enzyme-independent pathways. Such a process directly influences protein function and plays a crucial role in the regulation of gene expression. AARS mitochondrial alanyl-tRNA synthetase, Brg1 brahma-related gene 1, GLUT glucose transporter, HBO1 histone acetyltransferase binding to ORC-1, HDAC histone deacetylase, Kla lysine lactylation, LGSH lactyl-glutathione, MCT monocarboxylate transporter, P300 acetyltransferase p300, SIRT histone deacetylase sirtuin. Created with Figdraw.

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  Fig. 5. Lactylation in histone and nonhistone proteins: implications for ischemia-reperfusion injury. Lactylation in both histone and nonhistone proteins is a critical factor in several diseases linked to ischemia-reperfusion injury. This process significantly impacts organs and tissues such as the heart, liver, kidney, brain, and others, underscoring its importance in the pathophysiology of these conditions. Created with Figdraw.