{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T18:36:32Z","timestamp":1789497392322,"version":"build-2803163510"},"reference-count":66,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T00:00:00Z","timestamp":1758153600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Lily Foundation","award":["LILY-2017.18"],"award-info":[{"award-number":["LILY-2017.18"]}]},{"name":"Lily Foundation","award":["Bax_2023"],"award-info":[{"award-number":["Bax_2023"]}]},{"name":"Purine Patients Metabolic Association","award":["LILY-2017.18"],"award-info":[{"award-number":["LILY-2017.18"]}]},{"name":"Purine Patients Metabolic Association","award":["Bax_2023"],"award-info":[{"award-number":["Bax_2023"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is caused by pathogenic mutations in the nuclear TYMP gene, which encodes the cytosolic enzyme thymidine phosphorylase. In addition to the systemic accumulation of thymidine and deoxyuridine, several case studies have reported abnormalities in a range of other metabolites in patients with MNGIE. Since metabolites are intermediates or end-products of numerous biochemical reactions, they serve as highly informative indicators of an organism\u2019s metabolic activity. This study aimed to perform an untargeted metabolomic profiling to determine whether individuals with MNGIE exhibit a distinct plasma metabolic signature compared to 15 age- and sex-matched healthy controls. Metabolites were profiled using Ultra-High-Performance Liquid Chromatography\u2013Mass Spectrometry (UHPLC-MS). A total of 160 metabolites were found to be significantly upregulated and 260 downregulated in patients with MNGIE. KEGG pathway enrichment analysis revealed disruptions in 20 metabolic pathways, with arachidonic acid metabolism and bile acid biosynthesis being the most significantly upregulated. Univariate receiver operating characteristic (ROC) curve analyses identified 23 individual metabolites with diagnostic potential, each showing an area under the curve (AUC) \u2265 0.80. We propose that an impaired resolution of inflammation contributes to a chronic inflammatory state in MNGIE, potentially driving disease progression. Additionally, we suggest that the gut\u2013liver axis plays a central role in MNGIE pathophysiology, with hepatic function being bidirectionally influenced by gut-derived factors.<\/jats:p>","DOI":"10.3390\/ijms26189107","type":"journal-article","created":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T12:54:26Z","timestamp":1758200066000},"page":"9107","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Untargeted Plasma Metabolomics Extends the Biomarker Profile of Mitochondrial Neurogastrointestinal Encephalomyopathy"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6306-080X","authenticated-orcid":false,"given":"Bridget E.","family":"Bax","sequence":"first","affiliation":[{"name":"School of Health and Medical Sciences, City St George\u2019s, University of London, London SW17 0RE, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9574-7841","authenticated-orcid":false,"given":"Sema Kalkan","family":"U\u00e7ar","sequence":"additional","affiliation":[{"name":"Division of Metabolism and Nutrition, Department of Pediatrics, Ege University Medical Faculty, Izmir 35100, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1212\/WNL.44.4.721","article-title":"Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE): Clinical, Biochemical, and Genetic Features of an Autosomal Recessive Mitochondrial Disorder","volume":"44","author":"Hirano","year":"1994","journal-title":"Neurology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1126\/science.283.5402.689","article-title":"Thymidine Phosphorylase Gene Mutations in MNGIE, a Human Mitochondrial Disorder","volume":"283","author":"Nishino","year":"1999","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/S0960-8966(00)00159-0","article-title":"MNGIE: From Nuclear DNA to Mitochondrial DNA","volume":"11","author":"Nishino","year":"2001","journal-title":"Neuromuscul. Disord."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1097\/01.nrl.0000106919.06469.04","article-title":"Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE): A Disease of Two Genomes","volume":"10","author":"Hirano","year":"2004","journal-title":"Neurologist"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1913","DOI":"10.1172\/JCI17828","article-title":"Site-Specific Somatic Mitochondrial DNA Point Mutations in Patients with Thymidine Phosphorylase Deficiency","volume":"111","author":"Nishigaki","year":"2003","journal-title":"J. Clin. Investig."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3326","DOI":"10.1093\/brain\/awr245","article-title":"Clinical and Genetic Spectrum of Mitochondrial Neurogastrointestinal Encephalomyopathy","volume":"134","author":"Garone","year":"2011","journal-title":"Brain"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Pacitti, D., Levene, M., Garone, C., Nirmalananthan, N., and Bax, B.E. (2018). Mitochondrial Neurogastrointestinal Encephalomyopathy: Into the Fourth Decade, What We Have Learned So Far. Front. Genet., 9.","DOI":"10.3389\/fgene.2018.00669"},{"key":"ref_8","unstructured":"Hirano, M. (1993). Mitochondrial Neurogastrointestinal Encephalopathy Disease. GeneReviews\u00ae, University of Washington."},{"key":"ref_9","first-page":"547","article-title":"MNGIE Syndrome in 2 Siblings","volume":"153","author":"Debouverie","year":"1997","journal-title":"Rev. Neurol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1007\/s00431-010-1237-0","article-title":"Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE): Case Report with a New Mutation","volume":"169","year":"2010","journal-title":"Eur. J. Pediatr."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1007\/s10072-010-0225-5","article-title":"A Second MNGIE Patient without Typical Mitochondrial Skeletal Muscle Involvement","volume":"31","author":"Cardaioli","year":"2010","journal-title":"Neurol. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1007\/s10545-010-9049-y","article-title":"Biochemical Abnormalities in a Patient with Thymidine Phosphorylase Deficiency with Fatal Outcome","volume":"33","author":"Bakker","year":"2010","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1038\/ejhg.2013.148","article-title":"Large Copy Number Variations in Combination with Point Mutations in the TYMP and SCO2 Genes Found in Two Patients with Mitochondrial Disorders","volume":"22","author":"Zeman","year":"2014","journal-title":"Eur. J. Human. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.hemonc.2014.12.001","article-title":"Mitochondrial Neurogastrointestinal Encephalomyopathy Treated with Stem Cell Transplantation: A Case Report and Review of Literature","volume":"8","author":"Peedikayil","year":"2015","journal-title":"Hematol.\/Oncol. Stem Cell Ther."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.1007\/s00109-023-02358-9","article-title":"Distinctive Metabolic Remodeling in TYMP Deficiency beyond Mitochondrial Dysfunction","volume":"101","author":"Du","year":"2023","journal-title":"J. Mol. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.ccell.2015.12.004","article-title":"An Integrated Metabolic Atlas of Clear Cell Renal Cell Carcinoma","volume":"29","author":"Hakimi","year":"2016","journal-title":"Cancer Cell"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e9091","DOI":"10.15252\/emmm.201809091","article-title":"Metabolomes of Mitochondrial Diseases and Inclusion Body Myositis Patients: Treatment Targets and Biomarkers","volume":"10","author":"Buzkova","year":"2018","journal-title":"EMBO Mol. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e136055","DOI":"10.1172\/JCI136055","article-title":"Circulating Markers of NADH-Reductive Stress Correlate with Mitochondrial Disease Severity","volume":"131","author":"Sharma","year":"2021","journal-title":"J. Clin. Investig."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1571","DOI":"10.1073\/pnas.0906039107","article-title":"A Plasma Signature of Human Mitochondrial Disease Revealed through Metabolic Profiling of Spent Media from Cultured Muscle Cells","volume":"107","author":"Shaham","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1467","DOI":"10.1007\/s00109-020-01967-y","article-title":"Expanding and Validating the Biomarkers for Mitochondrial Diseases","volume":"98","author":"Maresca","year":"2020","journal-title":"J. Mol. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1055\/s-2002-33679","article-title":"Effects of Oral Creatine Supplementation in a Patient with MELAS Phenotype and Associated Nephropathy","volume":"33","author":"Barisic","year":"2002","journal-title":"Neuropediatrics"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.1002\/(SICI)1097-4598(199909)22:9<1299::AID-MUS24>3.0.CO;2-4","article-title":"Supplementation with Creatine Monohydrate in Children with Mitochondrial Encephalomyopathies","volume":"22","author":"Borchert","year":"1999","journal-title":"Muscle Nerve"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1502","DOI":"10.1002\/(SICI)1097-4598(199712)20:12<1502::AID-MUS4>3.0.CO;2-C","article-title":"A Randomized, Controlled Trial of Creatine Monohydrate in Patients with Mitochondrial Cytopathies","volume":"20","author":"Tarnopolsky","year":"1997","journal-title":"Muscle Nerve"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/S0887-8994(02)00469-1","article-title":"Effectiveness of Creatine Monohydrate in Mitochondrial Encephalomyopathies","volume":"28","author":"Komura","year":"2003","journal-title":"Pediatr. Neurol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1748","DOI":"10.1212\/WNL.55.11.1748","article-title":"A Placebo-Controlled Crossover Trial of Creatine in Mitochondrial Diseases","volume":"55","author":"Klopstock","year":"2000","journal-title":"Neurology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1111\/j.1468-1331.2004.00970.x","article-title":"Creatine Has No Beneficial Effect on Skeletal Muscle Energy Metabolism in Patients with Single Mitochondrial DNA Deletions: A Placebo-Controlled, Double-Blind 31P-MRS Crossover Study","volume":"12","author":"Kornblum","year":"2005","journal-title":"Eur. J. Neurol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1124\/molpharm.124.000995","article-title":"Probing the Chemical Space of Guanidino-Carboxylic Acids to Identify the First Blockers of the Creatine-Transporter-1","volume":"106","author":"Farr","year":"2024","journal-title":"Mol. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1002\/jimd.12300","article-title":"Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE): Position Paper on Diagnosis, Prognosis, and Treatment by the MNGIE International Network","volume":"44","author":"Hirano","year":"2021","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"138","DOI":"10.4103\/TROG_20113202_138","article-title":"An Interesting Case of Intestinal Pseudo-Obstruction: MNGIE","volume":"32","author":"Patel","year":"2011","journal-title":"Trop. Gastroenterol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Li, Y., Chvatal-Medina, M., Trillos-Almanza, M.C., Bourgonje, A.R., Connelly, M.A., Moshage, H., Bakker, S.J.L., de Meijer, V.E., Blokzijl, H., and Dullaart, R.P.F. (2024). Circulating Citrate Is Reversibly Elevated in Patients with End-Stage Liver Disease: Association with All-Cause Mortality. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms252312806"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e22546","DOI":"10.1096\/fj.202200135RR","article-title":"The Intestine Is a Major Contributor to Circulating Succinate in Mice","volume":"36","author":"Tong","year":"2022","journal-title":"FASEB J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1097\/MOT.0000000000000930","article-title":"The Impact of the Gut Microbiome on Liver Transplantation","volume":"26","author":"Duong","year":"2021","journal-title":"Curr. Opin. Organ. Transplant."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1002\/hep.24423","article-title":"Characterization of Fecal Microbial Communities in Patients with Liver Cirrhosis","volume":"54","author":"Chen","year":"2011","journal-title":"Hepatology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e148548","DOI":"10.1172\/JCI148548","article-title":"The Role of Itaconate in Host Defense and Inflammation","volume":"132","author":"Peace","year":"2022","journal-title":"J. Clin. Investig."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Yang, W., Wang, Y., Tao, K., and Li, R. (2023). Metabolite Itaconate in Host Immunoregulation and Defense. Cell Mol. Biol. Lett., 28.","DOI":"10.1186\/s11658-023-00503-3"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Coelho, C. (2022). Itaconate or How I Learned to Stop Avoiding the Study of Immunometabolism. PLoS Pathog., 18.","DOI":"10.1371\/journal.ppat.1010361"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1038\/s42255-023-00801-2","article-title":"Itaconic Acid Underpins Hepatocyte Lipid Metabolism in Non-Alcoholic Fatty Liver Disease in Male Mice","volume":"5","author":"Weiss","year":"2023","journal-title":"Nat. Metab."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Yamaguchi, A., Botta, E., and Holinstat, M. (2022). Eicosanoids in Inflammation in the Blood and the Vessel. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.997403"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Artru, F., McPhail, M.J.W., Triantafyllou, E., and Trovato, F.M. (2022). Lipids in Liver Failure Syndromes: A Focus on Eicosanoids, Specialized Pro-Resolving Lipid Mediators and Lysophospholipids. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.867261"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"132","DOI":"10.7762\/cnr.2015.4.2.132","article-title":"Nutrition Therapy for Mitochondrial Neurogastrointestinal Encephalopathy with Homozygous Mutation of the TYMP Gene","volume":"4","author":"Wang","year":"2015","journal-title":"Clin. Nutr. Res."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Barisic, A., Ljubas Kelecic, D., Vranesic Bender, D., Karas, I., Brinar, M., Miletic, V., and Krznaric, Z. (2022). Case Report: A Patient with Mitochondrial Neurogastrointestinal Encephalomyopathy and Chronic Intestinal Failure. Front. Nutr., 9.","DOI":"10.3389\/fnut.2022.983873"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1002\/ncp.10726","article-title":"Intensive Nutrition Support May Benefit Patients with a Rare Mitochondrial Disorder","volume":"37","author":"Kasti","year":"2022","journal-title":"Nutr. Clin. Pract."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"63","DOI":"10.62210\/ClinSciNutr.2025.104","article-title":"Nutritional Management in MNGIE Disease: A Case Report","volume":"7","author":"Kartal","year":"2025","journal-title":"Clin. Sci. Nutr."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Al-Shaer, A.E., Buddenbaum, N., and Shaikh, S.R. (2021). Polyunsaturated Fatty Acids, Specialized pro-Resolving Mediators, and Targeting Inflammation Resolution in the Age of Precision Nutrition. Biochim. Biophys. Acta Mol. Cell Biol. Lipids, 1866.","DOI":"10.1016\/j.bbalip.2021.158936"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"705","DOI":"10.5603\/EP.a2018.0072","article-title":"The Effects of Cannabinoids on the Endocrine System","volume":"69","author":"Borowska","year":"2018","journal-title":"Endokrynol. Pol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1961","DOI":"10.1053\/j.gastro.2010.06.064","article-title":"Splanchnic Balance of Free Fatty Acids, Endocannabinoids, and Lipids in Subjects with Nonalcoholic Fatty Liver Disease","volume":"139","author":"Westerbacka","year":"2010","journal-title":"Gastroenterology"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.ymgme.2020.03.001","article-title":"Successful Liver Transplantation in Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE)","volume":"130","author":"Kripps","year":"2020","journal-title":"Mol. Genet. Metab."},{"key":"ref_48","first-page":"1","article-title":"Mitochondrial Neurogastrointestinal Encephalomyopathy: Approaches to Diagnosis and Treatment","volume":"4","author":"Bax","year":"2020","journal-title":"J. Transl. Genet. Genom."},{"key":"ref_49","first-page":"5553","article-title":"Effects of Uridine and Thymidine on the Degradation of 5-Fluorouracil, Uracil, and Thymine by Rat Liver Dihydropyrimidine Dehydrogenase","volume":"45","author":"Tuchman","year":"1985","journal-title":"Cancer Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2761","DOI":"10.1111\/bcp.13719","article-title":"Food-Effect Study on Uracil and Dihydrouracil Plasma Levels as Marker for Dihydropyrimidine Dehydrogenase Activity in Human Volunteers","volume":"84","author":"Henricks","year":"2018","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"\u0160arenac, T.M., and Mikov, M. (2018). Bile Acid Synthesis: From Nature to the Chemical Modification and Synthesis and Their Applications as Drugs and Nutrients. Front. Pharmacol., 9.","DOI":"10.3389\/fphar.2018.00939"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1016\/S0022-2275(20)38314-0","article-title":"Identification of 3 Alpha,4 Beta,7 Alpha-Trihydroxy-5 Beta-Cholanoic Acid in Human Bile: Reflection of a New Pathway in Bile Acid Metabolism in Humans","volume":"30","author":"Dumaswala","year":"1989","journal-title":"J. Lipid Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.cca.2018.04.035","article-title":"Diagnostic and Therapeutic Profiles of Serum Bile Acids in Women with Intrahepatic Cholestasis of Pregnancy-a Pseudo-Targeted Metabolomics Study","volume":"483","author":"Cui","year":"2018","journal-title":"Clin. Chim. Acta"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1128\/aem.47.5.1167-1168.1984","article-title":"Absence of Transformation of Beta-Muricholic Acid by Human Microflora Implanted in the Digestive Tracts of Germfree Male Rats","volume":"47","author":"Sacquet","year":"1984","journal-title":"Appl. Environ. Microbiol."},{"key":"ref_55","first-page":"G835","article-title":"Protection against Hydrophobic Bile Salt-Induced Cell Membrane Damage by Liposomes and Hydrophilic Bile Salts","volume":"264","author":"Sagawa","year":"1993","journal-title":"Am. J. Physiol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1111\/j.1365-2362.1989.tb00246.x","article-title":"Unconjugated Serum Bile Acids as a Marker of Small Intestinal Bacterial Overgrowth","volume":"19","author":"Masclee","year":"1989","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1811","DOI":"10.1002\/hep.32568","article-title":"Metabolic Reprogramming of the Intestinal Microbiome with Functional Bile Acid Changes Underlie the Development of NAFLD","volume":"76","author":"Smirnova","year":"2022","journal-title":"Hepatology"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1095\/biolreprod.110.087460","article-title":"ATP Synthesis, Mitochondrial Function, and Steroid Biosynthesis in Rodent Primary and Tumor Leydig Cells","volume":"84","author":"Midzak","year":"2011","journal-title":"Biol. Reprod."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"3286","DOI":"10.1128\/MCB.01742-08","article-title":"All-Trans-Retinoic Acid Represses Obesity and Insulin Resistance by Activating Both Peroxisome Proliferation-Activated Receptor Beta\/Delta and Retinoic Acid Receptor","volume":"29","author":"Berry","year":"2009","journal-title":"Mol. Cell Biol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"5325","DOI":"10.1210\/en.2006-0760","article-title":"Remodeling of White Adipose Tissue after Retinoic Acid Administration in Mice","volume":"147","author":"Mercader","year":"2006","journal-title":"Endocrinology"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.2337\/db15-1315","article-title":"Retinoic Acid Mediates Visceral-Specific Adipogenic Defects of Human Adipose-Derived Stem Cells","volume":"65","author":"Takeda","year":"2016","journal-title":"Diabetes"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Gautheron, J., Lima, L., Akinci, B., Zammouri, J., Auclair, M., Ucar, S.K., Ozen, S., Altay, C., Bax, B.E., and Nemazanyy, I. (2022). Loss of Thymidine Phosphorylase Activity Disrupts Adipocyte Differentiation and Induces Insulin-Resistant Lipoatrophic Diabetes. BMC Med., 20.","DOI":"10.1186\/s12916-022-02296-2"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/0022-510X(76)90236-7","article-title":"Congenital Oculoskeletal Myopathy with Abnormal Muscle and Liver Mitochondria","volume":"27","author":"Okamura","year":"1976","journal-title":"J. Neurol. Sci."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Wen, B., Mei, Z., Zeng, C., and Liu, S. (2017). MetaX: A Flexible and Comprehensive Software for Processing Metabolomics Data. BMC Bioinformatics, 18.","DOI":"10.1186\/s12859-017-1579-y"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/s11306-016-1030-9","article-title":"Non-Targeted UHPLC-MS Metabolomic Data Processing Methods: A Comparative Investigation of Normalisation, Missing Value Imputation, Transformation and Scaling","volume":"12","author":"Engel","year":"2016","journal-title":"Metabolomics"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1038\/nprot.2011.335","article-title":"Procedures for Large-Scale Metabolic Profiling of Serum and Plasma Using Gas Chromatography and Liquid Chromatography Coupled to Mass Spectrometry","volume":"6","author":"Dunn","year":"2011","journal-title":"Nat. Protoc."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/18\/9107\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:47:54Z","timestamp":1760035674000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/18\/9107"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,18]]},"references-count":66,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["ijms26189107"],"URL":"https:\/\/doi.org\/10.3390\/ijms26189107","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,18]]}}}