Cardiology · Medical Literature
SIRT3 in post-myocardial infarction macrophage reprogramming: linking mitochondrial fitness to inflammation resolution and repair.
Abstract
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.
Clinical relevance
Despite advances in reperfusion therapy and pharmacotherapy, persistent post-MI inflammation and adverse ventricular remodeling remain major drivers of poor long-term outcomes, representing an unmet therapeutic target. This review addresses the mechanistic gap between macrophage immunometabolism and infarct healing by proposing SIRT3—the principal mitochondrial NAD⁺-dependent deacetylase—as a central regulatory node governing macrophage state transitions after MI. Cardiologists should engage with this framework now as it lays experimentally tractable groundwork for mitochondrial-targeted and macrophage-specific interventions in post-infarction cardiac repair.
Key findings
1. The conventional M1/M2 macrophage dichotomy is insufficient to capture the dynamic, phenotypically heterogeneous, and metabolically constrained macrophage states that emerge during infarct healing; a trajectory-based reprogramming framework is proposed as a more accurate paradigm. 2. Mitochondrial fitness—encompassing glycolytic rewiring, TCA cycle remodeling, mtROS accumulation, OXPHOS, FAO, and mitochondrial quality control—is identified as a critical determinant governing the macrophage transition from sustained inflammation to reparative resolution. 3. A staged dual-axis working model is advanced: the SOD2–mtROS axis is more closely linked to early nonresolving inflammation, while the PDHA1–metabolic flexibility axis is posited to be more relevant to efferocytosis-associated reparative transition. 4. NAD⁺ availability is highlighted as an upstream limiting factor that may constrain SIRT3 activity in macrophages under ischemic-inflammatory stress, positioning NAD⁺ repletion as a potential therapeutic lever. 5. SIRT3 is proposed to link mitochondrial protein acetylation status to macrophage phenotypic state transitions post-MI, functioning as a nodal integrator of mitochondrial fitness and immunological output. 6. The authors critically acknowledge that macrophage-specific causal evidence for SIRT3 in MI remains sparse, that the evidence base is largely indirect and convergent, and that the proposed framework should be regarded as a testable working hypothesis rather than a settled causal model.
Practice implications
While no direct clinical practice changes are mandated by this mechanistic review, clinicians and translational researchers should recognize macrophage immunometabolism—particularly mitochondrial NAD⁺/SIRT3 signaling—as an emerging therapeutic axis in post-MI cardiac repair that warrants prospective investigation. Future interventional strategies targeting this pathway (e.g., NAD⁺ precursor supplementation, mitochondria-directed SIRT3 activators) will require careful attention to timing relative to infarction, cellular specificity of delivery, and robust target engagement biomarkers before clinical application. The authors' explicit caution regarding human translatability and the current evidence hierarchy should temper enthusiasm and reinforce the need for macrophage-specific causal studies in relevant preclinical MI models prior to any trial design.