{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T20:07:26Z","timestamp":1789848446036,"version":"4.0.1"},"reference-count":44,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,28]],"date-time":"2025-12-28T00:00:00Z","timestamp":1766880000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["RS-2025-00518438"],"award-info":[{"award-number":["RS-2025-00518438"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["RS-2023-00217567"],"award-info":[{"award-number":["RS-2023-00217567"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Sepsis induces severe immune and metabolic dysfunction driven by mitochondrial failure. Mitochondrial transplantation (MT) has emerged as a promising strategy to restore mitochondrial bioenergetics, but its metabolic impact on immune cells remains unclear. Here, we used gas chromatography\u2013time-of-flight mass spectrometry (GC-TOF-MS)-based metabolomics to evaluate metabolic alterations in peripheral blood mononuclear cells (PBMCs) and splenocytes from a rat polymicrobial sepsis model treated with MT. Principal component and partial least-squares discriminant analyses revealed distinct clustering between sham, sepsis, and MT groups. Sepsis markedly suppressed metabolites related to amino acid, carbohydrate, and lipid metabolism, including aspartic acid, glutamic acid, AMP, and myo-inositol, reflecting mitochondrial metabolic paralysis. MT partially restored these metabolites toward sham levels, reactivating tricarboxylic acid (TCA) cycle, nucleotide, and lipid pathways. Pathway analysis confirmed that exogenous mitochondria reversed sepsis-induced metabolic suppression and promoted bioenergetic recovery in immune cells. These findings provide direct metabolomic evidence that MT reprograms immune metabolism and restores oxidative and biosynthetic function during sepsis, supporting its potential as a mitochondrial-based metabolic therapy.<\/jats:p>","DOI":"10.3390\/ijms27010332","type":"journal-article","created":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T06:25:51Z","timestamp":1766989551000},"page":"332","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Mitochondrial Transplantation Restores Immune Cell Metabolism in Sepsis: A Metabolomics Study"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3537-4136","authenticated-orcid":false,"given":"Tae Nyoung","family":"Chung","sequence":"first","affiliation":[{"name":"Department of Emergency Medicine, CHA University School of Medicine, 59 Yatap-Ro, Bundang-gu, Seongnam-si 13496, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Se Rin","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Bioscience and Biotechnology, Konkuk University, Seoul 05029, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Su-Hyun","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Bioscience and Biotechnology, Konkuk University, Seoul 05029, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Choong Hwan","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Bioscience and Biotechnology, Konkuk University, Seoul 05029, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7991-9428","authenticated-orcid":false,"given":"Kyuseok","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, CHA University School of Medicine, 59 Yatap-Ro, Bundang-gu, Seongnam-si 13496, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2133","DOI":"10.1056\/NEJMra2403213","article-title":"Sepsis and Septic Shock","volume":"391","author":"Meyer","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1001\/jama.2016.0287","article-title":"The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)","volume":"315","author":"Singer","year":"2016","journal-title":"JAMA"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e2013","DOI":"10.1016\/S2214-109X(25)00356-0","article-title":"Global, regional, and national sepsis incidence and mortality, 1990\u20132021: A systematic analysis","volume":"13","author":"Collaborators","year":"2025","journal-title":"Lancet Glob. Health"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"185","DOI":"10.15441\/ceem.25.174","article-title":"Epidemiology of sepsis in emergency departments: Insights from the National Emergency Department Information System (NEDIS) database in Korea, 2018\u20132022","volume":"12","author":"Shin","year":"2025","journal-title":"Clin. Exp. Emerg. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.1002\/JLB.3MR0322-692RR","article-title":"Sepsis, pyruvate, and mitochondria energy supply chain shortage","volume":"112","author":"McCall","year":"2022","journal-title":"J. Leukoc. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1042\/CS20220869","article-title":"Essential metabolism required for T and B lymphocyte functions: An update","volume":"137","author":"Diniz","year":"2023","journal-title":"Clin. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Ferreira, B.L., Sousa, M.B., Leite, G.G.F., Brunialti, M.K.C., Nishiduka, E.S., Tashima, A.K., van der Poll, T., and Salomao, R. (2022). Glucose metabolism is upregulated in the mononuclear cell proteome during sepsis and supports endotoxin-tolerant cell function. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.1051514"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.coi.2014.01.006","article-title":"Metabolism of activated T lymphocytes","volume":"27","author":"Maciolek","year":"2014","journal-title":"Curr. Opin. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"102968","DOI":"10.1016\/j.redox.2023.102968","article-title":"Restoring the infected powerhouse: Mitochondrial quality control in sepsis","volume":"68","author":"Gartzke","year":"2023","journal-title":"Redox Biol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Merz, T.M., Pereira, A.J., Schurch, R., Schefold, J.C., Jakob, S.M., Takala, J., and Djafarzadeh, S. (2017). Mitochondrial function of immune cells in septic shock: A prospective observational cohort study. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0178946"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1097\/SHK.0000000000001486","article-title":"Mitochondrial Dysfunction is Associated with an Immune Paralysis Phenotype in Pediatric Sepsis","volume":"54","author":"Weiss","year":"2020","journal-title":"Shock"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"20925","DOI":"10.1039\/D4NR02471K","article-title":"Encapsulated mitochondria to reprogram the metabolism of M2-type macrophages for anti-tumor therapy","volume":"16","author":"Wang","year":"2024","journal-title":"Nanoscale"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1016\/j.cmet.2016.04.007","article-title":"Mitochondrial Transfer by Photothermal Nanoblade Restores Metabolite Profile in Mammalian Cells","volume":"23","author":"Wu","year":"2016","journal-title":"Cell Metab."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1186\/s13054-020-03436-x","article-title":"The immune modulatory effects of mitochondrial transplantation on cecal slurry model in rat","volume":"25","author":"Hwang","year":"2021","journal-title":"Crit. Care"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1097\/SHK.0000000000001681","article-title":"Muscle-Derived Mitochondrial Transplantation Reduces Inflammation, Enhances Bacterial Clearance, and Improves Survival in Sepsis","volume":"56","author":"Zhang","year":"2021","journal-title":"Shock"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1186\/s13578-022-00805-7","article-title":"Mitochondrial transfer\/transplantation: An emerging therapeutic approach for multiple diseases","volume":"12","author":"Liu","year":"2022","journal-title":"Cell Biosci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1819","DOI":"10.1152\/physrev.00035.2018","article-title":"Metabolomics for Investigating Physiological and Pathophysiological Processes","volume":"99","author":"Wishart","year":"2019","journal-title":"Physiol. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1186\/s13054-024-05069-w","article-title":"Mitochondrial dysfunction in sepsis: Mechanisms and therapeutic perspectives","volume":"28","author":"Hu","year":"2024","journal-title":"Crit. Care"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"McBride, M.A., Owen, A.M., Stothers, C.L., Hernandez, A., Luan, L., Burelbach, K.R., Patil, T.K., Bohannon, J.K., Sherwood, E.R., and Patil, N.K. (2020). The Metabolic Basis of Immune Dysfunction Following Sepsis and Trauma. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.01043"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"116032","DOI":"10.1016\/j.celrep.2025.116032","article-title":"Unraveling mitochondrial pyruvate dysfunction to mitigate hyperlactatemia and lethality in sepsis","volume":"44","author":"Nuyttens","year":"2025","journal-title":"Cell Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e78654","DOI":"10.7554\/eLife.78654","article-title":"Mitochondrial redox adaptations enable alternative aspartate synthesis in SDH-deficient cells","volume":"12","author":"Hart","year":"2023","journal-title":"Elife"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"8952","DOI":"10.1038\/s41467-025-64013-w","article-title":"Metabolic profiling reveals channeled de novo pyrimidine and purine biosynthesis fueled by mitochondrially generated aspartic acid in cancer cells","volume":"16","author":"Pareek","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1095","DOI":"10.1042\/CS20257631","article-title":"Physiological roles of phosphoinositides and inositol phosphates: Implications for metabolic dysfunction-associated steatotic liver disease","volume":"139","author":"Cheng","year":"2025","journal-title":"Clin. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"25633","DOI":"10.1038\/s41598-024-76527-2","article-title":"Antioxidant and anticoagulant properties of myo-inositol determined in an ex vivo studies and gas chromatography analysis","volume":"14","author":"Rolnik","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"159137","DOI":"10.1016\/j.bbalip.2022.159137","article-title":"Inositol depletion regulates phospholipid metabolism and activates stress signaling in HEK293T cells","volume":"1867","author":"Suliman","year":"2022","journal-title":"Biochim. Biophys. Acta Mol. Cell Biol. Lipids"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2765","DOI":"10.1002\/mrm.28286","article-title":"Estimating pentose phosphate pathway activity from the analysis of hepatic glycogen (13) C-isotopomers derived from [U-(13) C]fructose and [U-(13) C]glucose","volume":"84","author":"Belew","year":"2020","journal-title":"Magn. Reson. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3015","DOI":"10.1016\/j.jchromb.2010.09.004","article-title":"A plasma global metabolic profiling approach applied to an exercise study monitoring the effects of glucose, galactose and fructose drinks during post-exercise recovery","volume":"878","author":"Bruce","year":"2010","journal-title":"J. Chromatogr. B Analyt. Technol. Biomed. Life Sci."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Iizuka, K. (2023). Recent Progress on Fructose Metabolism-Chrebp, Fructolysis, and Polyol Pathway. Nutrients, 15.","DOI":"10.3390\/nu15071778"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Kim, Y.S., Lee, H.A.R., Lee, M.J., Park, Y.J., Mun, S., Yune, C.J., Chung, T.N., Bae, J., Kim, M.J., and Choi, Y.S. (2023). The Effects of Mitochondrial Transplantation on Sepsis Depend on the Type of Cell from Which They Are Isolated. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241210113"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3668","DOI":"10.1016\/j.clnu.2021.05.008","article-title":"Development and validation of a novel sepsis biomarker based on amino acid profiling","volume":"40","author":"Ahn","year":"2021","journal-title":"Clin. Nutr."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1186\/s12967-022-03320-y","article-title":"Integrative analysis of metabolomics and proteomics reveals amino acid metabolism disorder in sepsis","volume":"20","author":"Chen","year":"2022","journal-title":"J. Transl. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1038\/s41598-022-24878-z","article-title":"Metabolomics-based study of potential biomarkers of sepsis","volume":"13","author":"Li","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_33","first-page":"86","article-title":"Effects of imipenem and meropenem on purine content of endothelial cells","volume":"37","author":"Armbruster","year":"1999","journal-title":"Int. J. Clin. Pharmacol. Ther."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"130832","DOI":"10.1016\/j.bbagen.2025.130832","article-title":"Antibiotic-induced mitochondrial dysfunction: Exploring tissue-specific effects on HEI-OC1 cells and peripheral blood mononuclear cells","volume":"1869","author":"Liu","year":"2025","journal-title":"Biochim. Biophys. Acta Gen. Subj."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e70253","DOI":"10.1002\/mco2.70253","article-title":"Mitochondrial Transplantation: A Novel Therapeutic Approach for Treating Diseases","volume":"6","author":"Miao","year":"2025","journal-title":"MedComm (2020)"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Dubinin, M.V., Mikheeva, I.B., Stepanova, A.E., Igoshkina, A.D., Cherepanova, A.A., Semenova, A.A., Sharapov, V.A., Kireev, I.I., and Belosludtsev, K.N. (2024). Mitochondrial Transplantation Therapy Ameliorates Muscular Dystrophy in mdx Mouse Model. Biomolecules, 14.","DOI":"10.3390\/biom14030316"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"90","DOI":"10.5483\/BMBRep.2022-0108","article-title":"Primary astrocytic mitochondrial transplantation ameliorates ischemic stroke","volume":"56","author":"Lee","year":"2023","journal-title":"BMB Rep."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e099781","DOI":"10.1136\/bmjopen-2025-099781","article-title":"Non-linear relationship between ionised calcium and 28-day mortality in patients with sepsis: A retrospective cohort study from MIMIC-IV database","volume":"15","author":"Liang","year":"2025","journal-title":"BMJ Open"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"22761","DOI":"10.1038\/s41598-025-05090-1","article-title":"The association between ionized calcium level and 28-day mortality in patients with sepsis: A cohort study","volume":"15","author":"Niu","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1038\/s42255-024-01200-x","article-title":"Recommendations for mitochondria transfer and transplantation nomenclature and characterization","volume":"7","author":"Brestoff","year":"2025","journal-title":"Nat. Metab."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/j.jss.2016.08.054","article-title":"Dose-dependent mortality and organ injury in a cecal slurry peritonitis model","volume":"206","author":"Lee","year":"2016","journal-title":"J. Surg. Res."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Song, B.H., Son, S.Y., Kim, H.K., Ha, T.W., Im, J.S., Ryu, A., Jeon, H., Chung, H.Y., Oh, J.S., and Lee, C.H. (2020). Profiling of Metabolic Differences between Hematopoietic Stem Cells and Acute\/Chronic Myeloid Leukemia. Metabolites, 10.","DOI":"10.3390\/metabo10110427"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Ju, I.G., Lee, M.Y., Jeon, S.H., Huh, E., Kim, J.H., Lee, J.K., Lee, C.H., and Oh, M.S. (2020). GC-TOF-MS-Based Metabolomic Analysis and Evaluation of the Effects of HX106, a Nutraceutical, on ADHD-Like Symptoms in Prenatal Alcohol Exposed Mice. Nutrients, 12.","DOI":"10.3390\/nu12103027"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Son, S.Y., Park, Y.J., Jung, E.S., Singh, D., Lee, Y.W., Kim, J.G., and Lee, C.H. (2019). Integrated Metabolomics and Transcriptomics Unravel the Metabolic Pathway Variations for Different Sized Beech Mushrooms. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20236007"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/1\/332\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T06:26:26Z","timestamp":1766989586000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/1\/332"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,28]]},"references-count":44,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["ijms27010332"],"URL":"https:\/\/doi.org\/10.3390\/ijms27010332","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,28]]}}}