CD36-Pyruvate Kinase M2 Signaling Promotes Macrophage Phagocytosis Through Mitochondrial Reactive Oxygen Species

Zhang, J.; Chang, J.; Zhao, Y.; Beg, M. A.; Huang, W.; Vick, L.; Zhang, H.; Gupta, A.; Castleberry, M.; Zhang, Z.; Dai, W.; Zhu, J.; Yang, M.; Brown, A. K.; Xu, Z.; Ma, Y.-q.; Smith, B. C.; Zielonka, J.; Cui, W.; Zheng, Z.; Chen, Y.

doi:10.1101/2023.09.07.556574

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bioRxiv · 10.1101/2023.09.07.556574

CD36-Pyruvate Kinase M2 Signaling Promotes Macrophage Phagocytosis Through Mitochondrial Reactive Oxygen Species

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Abstract

Macrophage efferocytosis, the process by which phagocytes engulf and remove apoptotic cells (ACs), plays a critical role in maintaining tissue homeostasis. Efficient efferocytosis prevents secondary necrosis, mitigates chronic inflammation, and impedes atherosclerosis progression. However, the regulatory mechanisms of efferocytosis under atherogenic conditions remain poorly understood. We previously demonstrated that oxidized LDL (oxLDL), an atherogenic lipoprotein, induces mitochondrial reactive oxygen species (mtROS) in macrophages via CD36. In this study, we demonstrate that macrophage mtROS facilitate continual efferocytosis through a positive feedback mechanism. However, oxLDL disrupts continual efferocytosis by dysregulating the internalization of ACs. This disruption is mediated by an overproduction of mtROS. Mechanistically, oxLDL/CD36 signaling promotes the translocation of cytosolic PKM2 to mitochondria, facilitated by the chaperone GRP75. Mitochondrial PKM2 then binds to Complex III of the electron transport chain, inducing mtROS production. This study elucidates a novel regulatory mechanism of efferocytosis in atherosclerosis, providing potential therapeutic targets for intervention. SUMMARYMacrophages clear apoptotic cells through a process called efferocytosis, which involves mitochondrial ROS. However, the atherogenic oxidized LDL overstimulates mitochondrial ROS via the CD36-PKM2 pathway, disrupting continual efferocytosis. This finding elucidates a novel molecular mechanism that explains defects in efferocytosis, driving atherosclerosis progression.

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Zhang, J., Chang, J., Zhao, Y., Beg, M. A., Huang, W., Vick, L., Zhang, H., Gupta, A., Castleberry, M., Zhang, Z., Dai, W., Zhu, J., Yang, M., Brown, A. K., Xu, Z., Ma, Y.-q., Smith, B. C., Zielonka, J., Cui, W., Zheng, Z., Chen, Y.. 2023-09-08. CD36-Pyruvate Kinase M2 Signaling Promotes Macrophage Phagocytosis Through Mitochondrial Reactive Oxygen Species. https://doi.org/10.1101/2023.09.07.556574

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