SIRT3 in post-myocardial infarction macrophage reprogramming: linking mitochondrial fitness to inflammation resolution and repair

Le résumé fourni par la source

Myocardial infarction (MI) remains a leading cause of cardiovascular mortality worldwide. Despite significant advances in reperfusion strategies and pharmacotherapy, persistent inflammation and adverse ventricular remodeling continue to underlie poor long-term clinical outcomes. Macrophages serve as central orchestrators of post-MI healing, coordinating the clearance of necrotic debris, resolution of inflammation, remodeling of the extracellular matrix, and maturation of the fibrotic scar. However, the conventional M1/M2 dichotomy fails to fully capture the dynamic, phenotypically heterogeneous, and metabolically constrained macrophage states that emerge during infarct healing. In this review, we synthesize current evidence supporting a trajectory-based framework for macrophage reprogramming following MI and emphasize mitochondrial fitness as a critical determinant governing the transition from sustained inflammation to reparative resolution. We summarize key metabolic checkpoints regulating this functional shift—including glycolytic rewiring, tricarboxylic acid (TCA) cycle remodeling, mitochondrial reactive oxygen species (mtROS) accumulation, efferocytosis, oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO), and mitochondrial quality control. Furthermore, we advance the hypothesis that SIRT3—the principal mitochondrial NAD + -dependent deacetylase—may act as a central regulatory node linking mitochondrial protein acetylation to macrophage state transitions after MI. Specifically, we outline a staged dual-axis working model, generated from convergent but largely indirect evidence, in which the SOD2–mtROS axis is more closely linked to early nonresolving inflammation, whereas the PDHA1–metabolic flexibility axis may be more relevant to efferocytosis-associated reparative transition. We further highlight NAD + availability as an upstream limiting factor that may constrain SIRT3 activity in macrophages under ischemic-inflammatory stress. Finally, we critically evaluate the current evidence hierarchy, human translatability, therapeutic strategies, and key translational challenges—emphasizing considerations of timing, cellular specificity, delivery modalities, and target engagement. Although macrophage-specific causal evidence in myocardial infarction (MI) remains sparse, this framework is intended as a mechanistically coherent and experimentally tractable working hypothesis to guide future investigations into macrophage immunometabolism and mitochondrial-targeted interventions in post-infarction cardiac repair. Accordingly, the proposed framework should be viewed as a testable working hypothesis rather than a settled causal model of macrophage fate control in MI.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.