Aug 2026· Journal of Inflammation Research· Vol 19· 0 citations· 70 references
Medicine
TL;DR
This framework separates association, susceptibility, execution, inflammatory release, tissue consequence, and therapeutic relevance when interpreting links among metabolic stress, mitochondrial stress, and RCD in sepsis.
Abstract
Abstract Sepsis is increasingly viewed as a disorder of inflammatory, metabolic, and mitochondrial homeostasis, but the path from metabolic disturbance to regulated cell death (RCD) and organ injury remains incompletely defined. Human studies show clinically meaningful metabolic and bioenergetic heterogeneity, while experimental models link mitochondrial stress, inflammatory signaling, membrane disruption, and pathway-specific RCD to tissue dysfunction. This review asks how evidence can be moved from co-occurrence toward mechanism. We synthesize findings across systemic metabolic phenotypes, cell-intrinsic immunometabolism, mitochondrial stress, RCD execution, membrane failure, inflammatory cargo release, organ injury, and therapeutic relevance. Apoptosis has the strongest direct human support as a non-lytic route of immune-cell depletion and epithelial loss; pyroptosis, ferroptosis, necroptosis, and PANoptosis are supported mainly by sepsis-relevant models and remain context dependent. Stronger mechanistic inference requires aligned measurements of metabolic flux, mitochondrial state, RCD execution, membrane integrity, extracellular cargo, host-defense effects, and tissue outcomes within matched cellular, organ, model, and temporal contexts. This framework separates association, susceptibility, execution, inflammatory release, tissue consequence, and therapeutic relevance when interpreting links among metabolic stress, mitochondrial stress, and RCD in sepsis.
Sepsis, defined as life-threatening organ dysfunction caused by a dysregulated host response to infection, remains a leading cause of mortality in critical care, and sepsis-associated multiple organ failure continues to defy effective therapy. Increasing evidence positions mitochondria at the interface of cellular bioenergetics and innate immune signaling, making mitochondrial immunometabolism a compelling framework for understanding sepsis pathophysiology. In this mini-review, we synthesize how mitochondrial bioenergetic dysfunction shapes immune cell function across the dynamic course of sepsis, from the glycolytic, oxidative phosphorylation (OXPHOS)-uncoupled state of the hyperinflammatory phase to the bioenergetic failure of the immunoparalytic phase. We examine the contested roles of mitochondrial quality-control mechanisms: mitophagy, dynamics, and biogenesis, in immune cell remodeling, and propose that their net effect follows a time- and cell-type-dependent pattern rather than a fixed protective or deleterious role. We further discuss how mitochondrial damage-associated molecular patterns (mtDAMPs), mitochondrial DNA (mtDNA), reactive oxygen species (mtROS), and remodeled cardiolipin activate the cGAS-STING pathway and the NLRP3 inflammasome and cross-regulate one another to amplify inflammation and drive organ injury. Integrating these themes, we highlight mitochondrial immunometabolic crosstalk between key immune cell subsets (macrophages, neutrophils, and lymphocytes) and the parenchymal cells of vulnerable target organs (heart, kidney, lung, and the gut–liver axis). Finally, we identify knowledge gaps spanning temporal dynamics, cellular heterogeneity, and clinical translation, acknowledge the limitations of the current evidence, and outline emerging therapeutic and monitoring strategies. Collectively, mitochondrial immunometabolism links immune cell dysfunction to organ failure and may guide stage- and endotype-specific interventions in sepsis.
Xing-Zhan Zhang, Ling Zhao, Wei Fu et al.· Frontiers in Immunology· 0 citations
A better understanding of mitochondrial lipid metabolism mechanisms may support earlier recognition of metabolically distinct SICM phenotypes, improve the timing and selection of targeted interventions, and facilitate the development of more precise approaches to reducing sepsis-related cardiac injury and improving patient outcomes.
Wei Chen, Ze-Ze Zhao, Xiaoqian Zheng et al.· Lipids in Health and Disease· 0 citations
Chronic kidney disease (CKD) represents a major global health challenge, affecting more than 10% of the population and contributing substantially to morbidity and premature mortality. Growing evidence identifies oxidative stress and mitochondrial dysfunction as central drivers of renal injury and disease progression across diverse etiologies. The kidney is one of the most mitochondria-rich organs in the body, reflecting the high bioenergetic demands required for tubular reabsorption and metabolic homeostasis. Disruption of mitochondrial oxidative phosphorylation, excessive production of reactive oxygen species (ROS), and impaired mitochondrial quality control mechanisms promote tubular injury, inflammation, and fibrosis. In particular, dysfunction of the electron transport chain, activation of NADPH oxidase isoforms—especially NOX4—and alterations in mitochondrial dynamics create a vicious cycle of oxidative damage and bioenergetic failure. Emerging evidence highlights the importance of mitochondrial quality control pathways, including fusion–fission balance, PINK1/Parkin-mediated mitophagy, and mitochondrial biogenesis regulated by PGC-1α and TFAM. Additional mechanisms include ferroptosis, epigenetic regulation, mitochondrial DNA-mediated innate immune activation, and Na+/K+-ATPase-linked redox signaling. At the translational level, redox and mitochondrial biomarkers and targeted therapies are biologically compelling, but the evidence is uneven: most candidate biomarkers remain insufficiently standardized, and direct mitochondria-targeted interventions are supported predominantly by preclinical studies or small human proof-of-concept trials. This review therefore emphasizes not only mechanistic advances but also conflicting findings, model limitations, and the barriers that currently separate experimental efficacy from clinically meaningful CKD outcomes.
Federica De Luca, Dario Troise, Valentina Camporeale et al.· Antioxidants· 0 citations
Sepsis-induced liver injury (SILI) is a major contributor to organ dysfunction and is closely associated with increased morbidity and mortality in septic patients. However, conventional liver biochemical indicators often fail to capture early mitochondrial and metabolic disturbances that precede overt hepatic dysfunction, limiting timely diagnosis and targeted intervention. Emerging evidence indicates that mitochondrial impairment plays a central role not only in bioenergetic failure but also in coordinating immune–metabolic dysregulation during sepsis. In this review, we critically synthesize current knowledge on mitochondrial injury in SILI, with a focus on its mechanistic links to cellular metabolic reprogramming, redox imbalance, and immune cell dysfunction. We highlight how these interconnected processes contribute to hepatocellular injury and disease progression. Furthermore, we summarize recently identified mitochondrial- and metabolism-associated biomarkers that show promise for earlier detection of liver dysfunction in sepsis. Rather than viewing mitochondrial dysfunction as an isolated event, we emphasize its role as a central mediator connecting metabolic stress and immune responses in the septic liver. This perspective provides a mechanistic basis for understanding disease heterogeneity and may facilitate the development of more precise diagnostic and therapeutic strategies.
Yi Wang, Ping-Sen Zhao· Frontiers in Cellular and In...· 0 citations
Sepsis-associated acute kidney injury (SA-AKI) is a common and severe complication in critically ill patients, independently associated with significantly increased mortality and a high risk of progression to chronic kidney disease. The pathogenesis of SA-AKI is complex and involves not only traditional concepts such as renal hypoperfusion, microcirculatory dysfunction, and direct tubular injury, but also, more importantly, the disordered activation of the host immune response. In recent years, regulated cell death (RCD) has emerged as a central mechanism linking immune dysregulation to tissue damage in SA-AKI. Unlike accidental cell death, RCD is orchestrated by genetically encoded molecular machinery, offering potential targets for therapeutic intervention. This review systematically summarizes the distinct molecular mechanisms of five major RCD pathways, including apoptosis, pyroptosis, necroptosis, autophagy, and ferroptosis, in the pathogenesis of SA-AKI. We highlight the specific contributions of each pathway, their regulatory networks, and the critical molecular players involved. Importantly, we delve into the intricate crosstalk among these pathways, such as caspase-8 acting as a molecular switch between apoptosis, pyroptosis, and necroptosis, the synergistic interplay between Gasdermin D and mixed lineage kinase domain-like protein, the role of autophagy as a “gatekeeper” for other RCDs, the concept of ferritinophagy, and the shared upstream signals including pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), Toll-like receptor 4 (TLR4), and oxidative stress. Building upon this mechanistic framework, we further evaluate the current state and future potential of targeted therapeutic strategies aimed at modulating RCD pathways to mitigate renal injury in sepsis. Thus, this review pursues two complementary objectives: to provide a cohesive mechanistic synthesis of RCD crosstalk in SA-AKI, and to propose a theoretical foundation for developing novel, multi-targeted therapies.
Xi-long Liu, Lei Ma· Frontiers in Cell and Develo...· 0 citations
Oxidative stress and mitochondrial dysfunction were intimately linked processes driving aging and numerous human diseases. Mitochondria generating reactive oxygen species (ROS) during energy metabolism; physiological ROS levels are vital for cell signaling and adaptation. However, excessive ROS damage mitochondrial DNA (mtDNA), respiratory proteins, and membrane lipids, reducing ATP production, disturbing calcium balance, and impairing organelle function. In turn, damaged mitochondria produce more ROS and release mtDNA, activating inflammatory pathways such as cGAS-STING and NLRP3. Mitochondrial quality control mechanisms—fusion, fission, mitophagy, proteostasis, and PGC-1α-driven biogenesis—are essential for homeostasis. This review discusses the biochemical links between oxidative stress and mitochondrial dysfunction and their roles in cardiovascular disease, type 2 diabetes, neurodegeneration, metabolic liver disease, cancer, and aging. We summarize widely used biomarkers (F2-isoprostanes, oxidized nucleic acids, mitochondrial respiration, multi-omics) and current therapeutic strategies, including exercise-induced mitohormesis, NRF2 activation, mitochondria-targeted antioxidants (MitoQ), cardiolipin-targeting peptides (elamipretide), NAD⁺ restoration, and mitophagy enhancers (urolithin A). Although several approaches show biological promise, clinical outcomes remain variable. Future therapies must prioritize restoring mitochondrial quality and redox balance over simplistic ROS scavenging.
A. Abdulkader, A. M. Hussein· World Journal of Chemical an...· 0 citations
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