Faculty Collaboration Database

Oxidized LDL stimulates PKM2-mediated mtROS production and phagocytosis. J Lipid Res 2025 May;66(5):100809

Date

04/19/2025

Pubmed ID

40250804

Pubmed Central ID

PMC12142535

DOI

10.1016/j.jlr.2025.100809

Scopus ID

2-s2.0-105006766220 (requires institutional sign-in at Scopus site)   6 Citations

Abstract

Oxidized low-density lipoprotein (oxLDL) promotes proatherogenic phenotypes in macrophages, accelerating the progression of atherosclerosis. Our previous studies demonstrated that oxLDL binds to its receptor CD36, stimulating mitochondrial reactive oxygen species (mtROS), which are critical in atherosclerosis development. However, the mechanisms underlying mtROS induction and their effects on macrophage cellular functions remain poorly understood. Macrophages rely on phagocytosis to clear pathogens, apoptotic cells, or other particles, a process critical for tissue homeostasis. Dysregulated or excessive particle ingestion, a key step in phagocytosis, can lead to lipid overloading and foam cell formation, a hallmark of atherosclerosis. In this study, we showed that macrophages pretreated with oxLDL exhibit increased particle ingestion, a phagocytic response significantly attenuated in Cd36-null macrophages. Further investigations revealed that oxLDL-induced phagocytosis depends on mtROS, as their suppression inhibited the process. In vivo, atherosclerosis-prone Apoe-null mice on a high-fat diet exhibited increased mtROS levels and enhanced phagocytic activity in aortic foamy macrophages compared to those from chow diet-fed mice, supporting a role of mtROS in promoting lesional macrophage phagocytosis. Mechanistically, we identified a novel signaling pathway whereby oxLDL/CD36 interaction induces the translocation of the cytosolic enzyme pyruvate kinase muscle 2 (PKM2) to mitochondria. Disruption of PKM2 mitochondrial translocation using siRNA knockdown or a specific chemical inhibitor reduced mtROS production and attenuated oxLDL-induced phagocytosis. In conclusion, our findings reveal a novel oxLDL-CD36-PKM2 signaling axis that drives mtROS production and phagocytosis in atherogenic macrophages.

Author List

Zhang J, Chang J, Chen V, Beg MA, Huang W, Vick L, Wang Y, Zhang H, Yttre E, Gupta A, Castleberry M, Zhang Z, Dai W, Zhu J, Song S, Yang M, Brown AK, Xu Z, Ma YQ, Smith BC, Zielonka J, Traylor JG Jr, Ben Dhaou C, Orr AW, Cui W, Chen Y

Authors

Yiliang Chen PhD Assistant Professor in the Medicine department at Medical College of Wisconsin
Brian C. Smith PhD Associate Professor in the Biochemistry department at Medical College of Wisconsin
Jacek M. Zielonka PhD Assistant Professor in the Biophysics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Atherosclerosis
CD36 Antigens
Carrier Proteins
Humans
Lipoproteins, LDL
Macrophages
Male
Membrane Proteins
Mice
Mice, Inbred C57BL
Mitochondria
Phagocytosis
Pyruvate Kinase
Reactive Oxygen Species
Thyroid Hormones