Sepsis, a life-threatening condition characterized by organ dysfunction resulting from severe infection, has gained considerable attention for the involvement of mitochondrial (mt) dysfunction in disrupting cellular energy metabolism and exacerbating inflammatory injury through the release of mt components. During sepsis, damage to the mt electron transport chain (ETC) in various organs impairs the mitochondria's ability to sustain ATP production and effectively use oxygen. This dysfunction also increases mt membrane permeability, releasing mt damage-associated molecular patterns (DAMPs), i.e., proteins, phospholipids, metabolites, nucleic acids (NA), and reactive oxygen species (ROS). These DAMPs synergize with pathogen-associated molecular patterns (PAMPs) to amplify systemic inflammation and organ injury. Despite advances in understanding mt-driven metabolic and immune dysregulation, translating these insights into effective therapeutic interventions remains challenging. This review explores the dual role of mitochondria in sepsis, functioning both as central regulators of cellular metabolism and as key modulators of inflammatory responses. It evaluates mt-targeted therapeutic strategies, including metabolic reprogramming, induction of mt biogenesis, antioxidant approaches, and stabilization of mt membranes. Integrating findings from both preclinical and clinical studies highlights potential therapeutic avenues to alleviate sepsis-induced organ dysfunction and improve patient outcomes.

Background: Metabolic modifications underlying human brain aging still remains poorly investigated. This study aims to reveal the differential metabolite profile of cerebrospinal fluid (CSF) in the aging group, and demonstrate the metabolic drift in the cerebroventricular environment of human aging brain. Methods: Ten patients aged from 25 to 35 years old as the control group, and an identical number of patients aged from 70 to 80 years old as the aging group, who go through surgery without diagnosed aging-related neurological diseases, are enrolled in this study. CSF is collected prior to spinal anesthesia. Then, we conduct an untargeted metabolomics analysis of CSF samples, 10 specimens for each group, through using the Agilent 1,290 Infinity LC system. The stability of the instrument, the repeatability of the experiment, and the reliability of data are evaluated. Raw data are normalized and subjected to the subsequent analysis by R package (ropls). Differentially accumulated metabolites with a variable importance in projection greater than 1.0 are validated by Student's t -test. Results: A total of 1,041 metabolic features are obtained, and 33 differentially accumulated metabolites are identified from the control and aging groups. The instrument analysis system is tested to show a good stability, and acquired data are verified to be stable and reliable. The top three enriched chemical classifications of metabolites are lipids and lipid-like molecules, organic acids and derivatives, and organoheterocyclic compounds. Next, differentially accumulated metabolites are analysed under both patterns. Nepodin, Fa 18:2 + 1o, and L-threonate are significantly downregulated, and chlorophene, resorcinol, and isethionate are upregulated in the aging group compared to controls under the negative ion pattern. Notably, creatine, sarcosine, and N-stearoylsphinganine are upregulated in the positive ion pattern. Regulation of differentially accumulated metabolites is revealed. These differential metabolites are potentially involved in some overlapping pathways, including ABC transporters, protein digestion and absorption, and glycine, serine, and threonine metabolism. Conclusions: This untargeted metabolomics study identified age-associated differences in CSF metabolites, with enrichment in potential pathways such as ABC transporters and glycine, serine, and threonine metabolism. These preliminary findings require confirmation in larger, independently validated cohorts.