Mechanisms and targeted intervention strategies of macrophage mitochondrial quality control imbalance in the progression of atherosclerosis
- 1Jiaxing Hospital of Traditional Chinese Medicine, Jiaxing University, Jiaxing, Zhejiang, China
- 2Zhejiang Chinese Medical University, Hangzhou, China
Abstract
Atherosclerosis (AS) is a vascular disease characterized by lipid accumulation, chronic inflammation, and plaque instability, which can lead to severe cardiovascular events, such as myocardial infarction and stroke. Macrophages are the predominant immune cells within plaques and form foam cells upon uptake of oxidized low-density lipoprotein, a critical driver of AS progression. Recent studies have confirmed that imbalance of the mitochondrial quality control (MQC) system participates in the initiation and progression of AS; however, the imbalance in macrophage MQC as an upstream regulatory mechanism has not yet been systematically elucidated. MQC encompasses mitophagy, fusion-fission balance, mitochondrial biogenesis, and mitochondrial DNA (mtDNA) homeostasis. This imbalance can result in impaired clearance of damaged mitochondria, dysfunction of the electron transport chain, and excessive production of reactive oxygen species (ROS), which in turn activate the NLRP3 inflammasome and trigger inflammation and apoptosis. Concurrently, mitochondrial metabolic reprogramming can promote macrophage polarization toward the pro-inflammatory M1 phenotype while suppressing the anti-inflammatory M2 phenotype, thereby exacerbating lipid deposition and inflammatory amplification. Plaque macrophages are, however, heterogeneous: TREM2-high foamy macrophages are typically less inflammatory and metabolically distinct from adjacent non-foamy macrophages, cautioning against a purely linear glycolysis-M1-foam-cell sequence. Current research predominantly focuses on MQC imbalance, whereas a systematic integration of how imbalances in the MQC network mediate macrophage inflammation, foam cell formation, and plaque progression remains lacking. Intervention strategies targeting mitophagy activation, restoration of mitochondrial fusion-fission homeostasis, mitochondrial antioxidant defense, and macrophage-targeted delivery have demonstrated potential for alleviating plaque burden and stabilizing vulnerable plaques in preclinical studies. This review systematically summarizes the role and molecular mechanisms of macrophage MQC imbalance in AS, outlines existing controversies, research gaps, and novel targeted intervention strategies, and provides a theoretical basis for the development of new therapeutic targets for AS prevention and treatment.
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BibTeX
@article{zhili2026mechanisms,
title = {{Mechanisms and targeted intervention strategies of macrophage mitochondrial quality control imbalance in the progression of atherosclerosis}},
author = {Guo Zhili and Zhu Xiaoyu},
journal = {Frontiers in Physiology},
year = {2026},
month = oct,
doi = {10.3389/fphys.2026.1975785},
url = {https://doi.org/10.3389/fphys.2026.1975785},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Mechanisms and targeted intervention strategies of macrophage mitochondrial quality control imbalance in the progression of atherosclerosis
AU - Guo Zhili
AU - Zhu Xiaoyu
PY - 2026
DA - 2026/10/22
JO - Frontiers in Physiology
DO - 10.3389/fphys.2026.1975785
UR - https://doi.org/10.3389/fphys.2026.1975785
AB - Atherosclerosis (AS) is a vascular disease characterized by lipid accumulation, chronic inflammation, and plaque instability, which can lead to severe cardiovascular events, such as myocardial infarction and stroke. Macrophages are the predominant immune cells within plaques and form foam cells upon uptake of oxidized low-density lipoprotein, a critical driver of AS progression. Recent studies have confirmed that imbalance of the mitochondrial quality control (MQC) system participates in the initiation and progression of AS; however, the imbalance in macrophage MQC as an upstream regulatory mechanism has not yet been systematically elucidated. MQC encompasses mitophagy, fusion-fission balance, mitochondrial biogenesis, and mitochondrial DNA (mtDNA) homeostasis. This imbalance can result in impaired clearance of damaged mitochondria, dysfunction of the electron transport chain, and excessive production of reactive oxygen species (ROS), which in turn activate the NLRP3 inflammasome and trigger inflammation and apoptosis. Concurrently, mitochondrial metabolic reprogramming can promote macrophage polarization toward the pro-inflammatory M1 phenotype while suppressing the anti-inflammatory M2 phenotype, thereby exacerbating lipid deposition and inflammatory amplification. Plaque macrophages are, however, heterogeneous: TREM2-high foamy macrophages are typically less inflammatory and metabolically distinct from adjacent non-foamy macrophages, cautioning against a purely linear glycolysis-M1-foam-cell sequence. Current research predominantly focuses on MQC imbalance, whereas a systematic integration of how imbalances in the MQC network mediate macrophage inflammation, foam cell formation, and plaque progression remains lacking. Intervention strategies targeting mitophagy activation, restoration of mitochondrial fusion-fission homeostasis, mitochondrial antioxidant defense, and macrophage-targeted delivery have demonstrated potential for alleviating plaque burden and stabilizing vulnerable plaques in preclinical studies. This review systematically summarizes the role and molecular mechanisms of macrophage MQC imbalance in AS, outlines existing controversies, research gaps, and novel targeted intervention strategies, and provides a theoretical basis for the development of new therapeutic targets for AS prevention and treatment.
SN - 1664-042X
ER -