Aug 2026· Biomolecules· Vol 16, pp. 1218· 0 citations· 194 references
Medicine
TL;DR
The potential of exercise to mitigate NLRP3 inflammasome-mediated inflammation and atrophy is promising, and the mechanisms underpinning inflammasome priming and activation, as well the effects of exercise are examined, with an emphasis on the skeletal muscle.
Abstract
Skeletal muscle mitochondria possess the ability to autoregulate their health and functioning by the orchestration of mitochondrial quality control (MQC) pathways. This plasticity allows them to adapt to various stimuli, such as exercise. However, under pathological conditions, mitochondria can become dysfunctional, generating damage-associated molecular patterns (DAMPs), such as reactive oxygen species (ROS) and oxidized mitochondrial DNA (mtDNA). These DAMPs can launch an innate immune response, with consequences of widespread inflammation and atrophy. Integral to this is the NLRP3 inflammasome complex. Activation of the NLRP3 inflammasome results in maturation of caspase-1, which processes pro-inflammatory cytokines IL-1β and IL-18, as well as GSDMD. Consequently, the pore-forming GSDMD-N fragment induces pyroptosis, releasing mature IL-1β and IL-18. Exercise training is widely accepted as a potent mechanism to promote skeletal muscle health, particularly by remodeling the mitochondrial network and reducing the production of DAMPs. It has also been shown promote an anti-inflammatory milieu with the release of various myokines. Indeed, the potential of exercise to mitigate NLRP3 inflammasome-mediated inflammation and atrophy is promising. This review will examine the mechanisms underpinning inflammasome priming and activation, as well the effects of exercise, with an emphasis on the skeletal muscle.
BACKGROUND
Heart failure is driven by pathological remodeling in which inflammation and mitochondrial dysfunction reinforce each other, yet the molecules that coordinate this interplay remain poorly defined. Netrin-3 is a guidance cue with no known function in the heart. We asked whether Netrin-3 acts in cardiomyocytes to affect mitochondrial integrity under inflammatory stress.
METHODS
We used neonatal rat cardiomyocytes treated with nigericin to activate the NLRP3 inflammasome. Netrin-3 was overexpressed via adenovirus or knocked down by siRNA. Its subcellular distribution was tracked by fractionation and by immunofluorescence. Mitochondrial morphology, Drp1 Ser616 phosphorylation, Mfn2 protein levels, and ROS production were quantified. Inflammasome activation was evaluated through caspase-1 cleavage, ASC speck formation, and IL-1β release. In mice with transverse aortic constriction, we delivered AAV9-shNetrin-3 or a neutralizing antibody and assessed cardiac function, tissue histology, and molecular markers.
RESULTS
NLRP3 activation increased Netrin-3 expression and its mitochondrial fraction content, a pattern supported by immunofluorescence colocalization with TOM20. Netrin-3 overexpression was associated with greater mitochondrial fragmentation, higher Drp1 phosphorylation, lower Mfn2, and increased mitochondrial ROS. Netrin-3 knockdown had the opposite effects on these parameters. ROS scavenging with N-acetylcysteine or MitoTEMPO attenuated the Netrin-3-associated increases in caspase-1 cleavage and IL-1β secretion. In pressure-overloaded hearts, Netrin-3 was upregulated; its genetic or pharmacological inhibition correlated with improved ejection fraction and reduced hypertrophy, fibrosis, and macrophage infiltration.
CONCLUSION
These observations support a model in which Netrin-3 participates in coupling inflammasome signaling to mitochondrial alterations through a ROS-dependent route. Whether Netrin-3 inhibition has therapeutic value in heart failure warrants further investigation.
Biao Li, Hao-Yang Ge, Xi-Wei Chen et al.· International Immunopharmaco...· 0 citations
Mitochondrial dysfunction occurs in response to a variety of causes. It leads to partial or complete inhibition of oxidative phosphorylation and, consequently, to the upregulation of fermentative glycolysis which remains the main or only energy-producing pathway. Mitochondrial dysfunction leads also to the release of several mediators, mainly oxidized mitochondrial DNA (mtDNA), reactive oxygen species (ROS) and adenosine triphosphate (ATP) molecules which have potent stimulatory effects on the innate immune system. In parallel, also upregulated glycolysis has immunomodulatory effects which are mediated by glycolytic enzymes or metabolites. In most cases these effects are unrelated to their role in metabolism and are referred to as non-canonical, “moonlighting” functions. In this article we propose that the immunomodulatory effects of upregulated glycolysis integrate those induced by the mediators released from damaged mitochondria (oxidized mtDNA, ROS, ATP). While many of these effects are immunostimulatory and act on both the innate as well as the adaptive immune system, some are immunosuppressive. The latter are likely induced in order to avoid excessive immunostimulatory effects with possible pathological consequences. Eventually, we address the relationship between upregulated fermentative glycolysis and another response promoted by dysfunctional mitochondria, i.e. the integrated stress response.
The NLRP3 inflammasome plays a pivotal role in innate immune responses and has emerged as an important contributor to the pathogenesis of cardiovascular diseases (CVDs), including atherosclerosis, heart failure, myocardial infarction, and hypertension-related organ damage. Upon activation, NLRP3 promotes the maturation and release of IL-1β and IL-18 and triggers pyroptosis, thereby exacerbating endothelial dysfunction, vascular smooth muscle cell proliferation and migration, lipid metabolic disorders, and adverse myocardial remodeling. These processes form a self-perpetuating cycle of inflammation and tissue injury. Therapeutic strategies targeting the NLRP3 pathway have progressed from non-specific anti-inflammatory agents, such as aspirin and colchicine, to more precise interventions that block NLRP3 oligomerization (e.g., MCC950 and its analogs), neutralize upstream cytokines, modulate metabolic and oxidative stress pathways, and employ advanced delivery systems including gene editing and nanocarriers. Despite these advances, current approaches are limited by insufficient target specificity, incomplete long-term safety data, and the absence of disease subtype-specific regimens. This review provides a comprehensive overview of multi-level therapeutic strategies directed against the NLRP3 inflammasome, critically evaluates preclinical and clinical evidence—including findings from the CANTOS trial—and discusses the translational potential of NLRP3-targeted immunometabolic therapy in CVDs. Looking forward, integration of multi-omics technologies, such as single-cell sequencing and spatial transcriptomics, with well-designed clinical studies will be essential to delineate the context-specific roles of NLRP3 across different CVD subtypes and to clarify its interactions with protective pathways such as AMPK and SIRT1. These efforts may facilitate the development of more selective, tissue-targeted, and safer therapeutic agents for the precision management of cardiovascular diseases.
Tian-Qing Zhang, Li Luo, Kai-Lin Yang et al.· Frontiers in Immunology· 1 citation
Preservation of mitochondrial integrity has emerged as a central hub in the anti-inflammatory effect of exercise. This narrative review advances a framework in which mitochondrial damage-associated molecular patterns (mtDAMPs) serve as the mechanistic bridge between exercise and inflammation. Mitochondrial dysfunction releases mtDAMPs, including mitochondrial DNA (mtDNA), reactive oxygen species, cardiolipin, N-formyl peptides, and ATP, which activate cGAS–STING, the NLRP3 inflammasome, TLR9, AIM2, ZBP1, and NF-κB signaling. Crosstalk among these pathways allows mild mitochondrial damage to escalate into chronic inflammation. Exercise opposes this cascade through the AMPK–PGC-1α axis, which coordinately activates four mitochondrial quality control (MQC) modules: biogenesis, antioxidant defense, dynamics, and mitophagy. The cardiovascular system illustrates this framework, as myocardial inflammation runs mainly through mtDNA–cGAS–STING signaling and vascular inflammation through oxidized mtDNA–NLRP3 signaling, while cardiovascular aging engages both axes at once. Throughout, exercise refers to repeated training rather than to a single bout, and the framework targets middle-aged and older adults with, or at risk of, cardiovascular disease. The upstream half of the sequence, in which training raises mitochondrial content and antioxidant capacity, rests on human muscle biopsy data; the downstream half remains largely preclinical. MQC is therefore proposed as a testable target rather than an established one.
This review elucidates the core mechanisms underpinning this dysfunction, including reactive oxygen species (ROS)-induced redox imbalance, mitochondrial DNA (mtDNA) damage accumulation, impaired mitophagy, and metabolic reprogramming, and critically examines how mitochondria act as signaling hubs for inter-organ crosstalk.
Mitochondria have long been viewed as the “powerhouses” of the cell, but research over the past decade has established that they play a far more complex role in skin immune homeostasis beyond ATP production. The metabolic preferences of immune cells and skin parenchymal cells—glycolysis, oxidative phosphorylation, or fatty acid oxidation—determine their fate choices during inflammatory responses. When mitochondrial function is impaired, the release of damage-associated molecular patterns (DAMPs) such as mitochondrial DNA and mitochondrial ROS can activate the cGAS-STING and NOD-like receptor family pyrin domain-containing 3 inflammasome pathways, driving inflammatory cycles in various skin diseases including psoriasis, atopic dermatitis, lupus erythematosus, and vitiligo. This review systematically examines the key mechanisms of mitochondrial metabolic reprogramming in skin immune disorders, focusing on 3 typical scenarios: the metabolic preferences of immune cells, mitochondrial DAMP-mediated autoinflammation, and the impact of mitochondrial dynamics imbalance on tissue-resident memory T cell function. Furthermore, we evaluate clinical evidence for repurposing old drugs such as metformin and thiazolidinediones, and discuss the translational prospects of emerging strategies including Nrf2 agonists, mitophagy inducers, and targeted nanocarriers. Understanding the “dual identity” of mitochondria in skin immunity—as both metabolic regulators and signaling sensors—will lay the foundation for developing precise metabolic immunomodulatory therapies.
Nan Chen, Xiang-Ping Xie, Shuang-Yan He et al.· Immune Network· 0 citations
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