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.
Abstract
Sepsis-induced cardiomyopathy (SICM) is a common and severe complication of sepsis that contributes substantially to circulatory instability, organ dysfunction, and adverse clinical outcomes. Mitochondrial dysfunction and metabolic reprogramming have emerged as central mechanisms underlying its pathogenesis. Because the adult myocardium depends heavily on mitochondrial lipid metabolism for continuous energy production, disruption of lipid metabolic homeostasis may critically impair myocardial bioenergetics and stress adaptation during sepsis.
Current evidence indicates that SICM is accompanied by extensive abnormalities in mitochondrial lipid metabolism, including impaired fatty acid uptake and oxidation, pathological cardiolipin remodeling, excessive lipid peroxidation, ferroptosis, disrupted lipid droplet–mitochondria interactions, and defective mitochondrial dynamics and quality control. These alterations interact with inflammatory signaling, redox imbalance, and metabolism-associated post-translational modifications, collectively promoting adenosine triphosphate (ATP) depletion, lipotoxicity, oxidative injury, and cardiac dysfunction.
This review summarizes the physiological organization of mitochondrial lipid metabolism in the healthy myocardium and systematically examines the mechanisms responsible for its dysregulation in SICM. Particular emphasis is placed on cardiolipin remodeling and mitochondrial membrane lipid homeostasis as potential links among impaired substrate oxidation, respiratory chain instability, oxidative stress amplification, and myocardial injury. Emerging therapeutic strategies aimed at restoring metabolic flexibility, preserving mitochondrial membrane integrity, limiting lipid peroxidation, and improving mitochondrial quality control are also evaluated. A better understanding of these 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.
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.
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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.
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This review examines mitochondrial pathology as the central orchestrator of SIC progression and integrates mitochondrial biology, immunometabolism, and translational medicine to identify promising directions for improving patient outcomes.
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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
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
Heart failure is a chronic cardiovascular syndrome with high morbidity and mortality worldwide, and its progression is closely linked to myocardial metabolic remodeling and disruption of mitochondrial homeostasis. Increasing evidence suggests that the gut microbiota and its metabolites represent an important interface between diet, inflammation, metabolic stress, and cardiovascular remodeling. Gut-derived metabolites, including short-chain fatty acids, trimethylamine N-oxide, tryptophan-derived metabolites, bile acids, phenylacetylglutamine, indoxyl sulfate, and urolithins, may influence myocardial mitochondrial homeostasis by affecting substrate oxidation, oxidative phosphorylation, reactive oxygen species production, inflammatory signaling, mitochondrial dynamics, mitophagy, and cell-death pathways. However, these metabolites should not be interpreted as uniformly protective or detrimental, because their biological effects may depend on concentration, exposure duration, bioavailability, protein binding, renal clearance, cellular targets, host metabotype, experimental model, and heart failure phenotype. Short-chain fatty acids and indole-3-propionic acid (IPA) have been linked to mitochondrial oxidative metabolism, nicotinamide adenine dinucleotide (NAD+)/sirtuin 3 (SIRT3)-related mitochondrial signaling, and inflammatory regulation in selected experimental settings, whereas the choline/trimethylamine N-oxide axis, indoxyl sulfate, phenylacetylglutamine, and dysregulated bile acid metabolism are associated with myocardial fibrosis, oxidative stress, mitochondrial dysfunction, and adverse outcomes. Nevertheless, many clinical associations may be influenced by renal dysfunction, disease severity, and heart-to-gut reverse causality, and many mechanistic findings remain derived from animal models, ex vivo systems, or non-classical heart-failure models. This narrative review summarizes current evidence linking gut-derived metabolites to myocardial mitochondrial homeostasis in heart failure, with emphasis on energy metabolic remodeling, oxidative stress, inflammation, mitochondrial quality control, cell death, and fibrotic remodeling. Potential intervention strategies targeting the gut microbiota and its metabolic pathways are also discussed with attention to their translational limitations and to the need for direct mitochondrial readouts, cell-type-specific validation, and phenotype-specific clinical studies.
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