Aug 2026· European Journal of Pharmacology· Vol 1033, pp.
179261
· 0 citations· 100 references
Medicine
TL;DR
Overall, MOTS-c represents a plausible but insufficiently validated molecule in SICM research, and its translational relevance will depend on disease-specific mechanistic and pharmacological validation.
Abstract
Sepsis-induced cardiomyopathy (SICM) is a prevalent cardiac complication of sepsis that is characterized by inflammatory dysregulation, mitochondrial dysfunction, metabolic disturbance, and changes in the myocardial microenvironment. Mitochondrial open reading frame of the 12S rRNA type-c (MOTS-c) is a mitochondrial-derived microprotein with metabolic regulatory and stress-responsive properties. Existing studies have linked MOTS-c to AMP-activated protein kinase-related energy metabolism, antioxidant responses, inflammatory restraint, endothelial and microvascular protection, and mitochondrial quality control. These processes are relevant to SICM; however, there is limited direct SICM-specific evidence for MOTS-c, and several proposed mechanisms, such as stress-responsive nuclear signaling, have been established primarily in non-SICM settings. This review summarizes the biological characteristics and stress-responsive regulation of MOTS-c, evaluates its potential involvement in pathological processes related to SICM, and distinguishes direct SICM evidence from findings extrapolated from other cardiovascular, metabolic, and inflammatory disease models. We also discuss the exploratory value and current limitations of MOTS-c as a stress-related adjunctive biomarker and potential therapeutic candidate, with particular attention to biomarker specificity, post-treatment efficacy, target-cell mechanisms, and pharmacokinetic or biodistribution issues under septic conditions. Overall, MOTS-c represents a plausible but insufficiently validated molecule in SICM research, and its translational relevance will depend on disease-specific mechanistic and pharmacological validation.
Sepsis-induced cardiomyopathy (SICM) is a frequent and clinically important complication of sepsis, characterized by acute and often reversible myocardial dysfunction and associated with poor outcomes in critically ill patients. Despite growing recognition of its clinical significance, effective mechanism-based therapies remain unavailable, largely because SICM is highly heterogeneous and driven by a complex interplay of inflammatory activation, endothelial and microcirculatory dysfunction, oxidative stress, mitochondrial injury, calcium-handling abnormalities, metabolic reprogramming, and dynamic cardiomyocyte adaptation. In recent years, increasing attention has been directed toward epigenetic regulation, as it provides a mechanistic framework linking septic stress to sustained transcriptional and post-transcriptional remodeling in the myocardium and its immune microenvironment. Numerous studies have therefore investigated epigenetic mechanisms in SICM, including DNA methylation, histone modifications, and non-coding RNA-mediated regulation. This review summarizes recent advances in the understanding of epigenetic mechanisms underlying SICM, with emphasis on their roles in inflammation, mitochondrial dysfunction, immune–cardiac crosstalk, and cardiomyocyte injury. We further discuss the translational relevance of epigenetic remodeling and highlight the emerging therapeutic potential of epigenetically targeted interventions. Collectively, these findings provide important mechanistic insights into SICM and may support the development of biomarker-guided stratification and more precise therapeutic strategies for septic myocardial dysfunction.
Chen Jiang, Zhan-Fei Li, Xi-Jie Dong et al.· International Journal of Mol...· 0 citations
Septic cardiomyopathy (SCM) is a prevalent and serious cardiac complication arising from sepsis-induced multiple organ dysfunction syndrome (MODS). The pathogenesis of SCM is complex and primarily involves immune-inflammatory responses, oxidative stress, programmed cell death, and mitochondrial dysfunction. In recent years, mitochondrial quality control (MQC) has attracted growing interest as a central mechanism for maintaining cellular homeostasis and myocardial energy metabolism in SCM. This review systematically summarizes recent advances in four key MQC mechanisms involved in SCM: (1) phosphatase and tensin homolog-induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy; (2) mitochondrial dynamics, including dynamin-related protein 1 (Drp1)/fission protein 1 (FIS1)-driven fission and optic atrophy protein 1 (OPA1)/mitofusin (MFN)-regulated fusion; (3) mitochondrial biogenesis under the regulatory control of the peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α)/nuclear respiratory factor 1 (NRF1)/mitochondrial transcription factor A (TFAM) axis; and (4) the mitochondrial unfolded protein response (UPRmt), which maintains mitochondrial proteostasis through mediators such as C/EBP homologous protein (CHOP), YME1-like protease (YME1L), and Overlapping activity with m-AAA protease 1 (OMA1). These mechanisms have been shown to work synergistically to regulate mitochondrial clearance, renewal, and functional maintenance. Any imbalance among them can exacerbate myocardial injury. This review also emphasizes the redox crosstalk between oxidative stress and immune inflammation, with an emphasis on the pivotal contributions of NADPH oxidase 2 (NOX2), high mobility group box 1 (HMGB1), and the nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome in vascular endothelial dysfunction and cardiac depression. In conclusion, preserving the dynamic equilibrium of MQC is crucial for preventing or reversing SCM and may present novel molecular targets and therapeutic strategies.
Xiang-Yi Pu, Zhao-Qi Yan, Zhi-Ming Liu et al.· Frontiers in Bioscience· 0 citations
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.
Guohairong Pan, Lulu Zhou, Ruochong Wang et al.· Journal of Inflammation Rese...· 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
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
Sepsis-induced myocardial dysfunction (SIMD) is a frequent and life-threatening complication of sepsis driven by interconnected inflammatory, oxidative, metabolic, and mitochondrial disturbances. Post-translational modifications (PTMs) have emerged as key regulators of these processes by dynamically altering protein activity, stability, localization, and signaling. This narrative review aimed to summarize the roles of major PTMs in SIMD and evaluate their potential as therapeutic targets. Relevant original studies and authoritative reviews published predominantly within the past decade were identified through targeted searches of PubMed and Web of Science and qualitatively synthesized. Current evidence indicates that phosphorylation, acetylation, ubiquitination, protein methylation, ADP-ribosylation, and palmitoylation regulate major pathways involved in myocardial inflammation, oxidative stress, mitochondrial dysfunction, metabolic reprogramming, apoptosis, and impaired contractility. Crosstalk among these modifications further integrates signaling networks, while upstream epigenetic mechanisms, including DNA methylation and N6-methyladenosine RNA modification, can influence PTM-related enzymes and downstream signaling. Experimental studies also suggest that pharmacological modulation of PTM-regulated pathways may attenuate myocardial injury; however, most mechanistic and therapeutic evidence derives from animal models and cultured cells, with limited validation in human septic myocardium. PTMs therefore represent promising mechanistic and therapeutic targets in SIMD, but systematic characterization of PTM crosstalk and rigorous human translational studies are required before PTM-directed strategies can be incorporated into clinical practice.
Xuan Liu, Hai-Hua Pan, Jun Cha et al.· Biomolecules & biomedicine· 0 citations
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
