{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T14:53:40Z","timestamp":1787496820288,"version":"build-2736575974"},"reference-count":49,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2023,3,22]],"date-time":"2023-03-22T00:00:00Z","timestamp":1679443200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32072807"],"award-info":[{"award-number":["32072807"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["2022YFD1300405"],"award-info":[{"award-number":["2022YFD1300405"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["32072807"],"award-info":[{"award-number":["32072807"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2022YFD1300405"],"award-info":[{"award-number":["2022YFD1300405"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Priority Academic Program Development of Jiangsu Higher Education Institutions","award":["32072807"],"award-info":[{"award-number":["32072807"]}]},{"name":"Priority Academic Program Development of Jiangsu Higher Education Institutions","award":["2022YFD1300405"],"award-info":[{"award-number":["2022YFD1300405"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Various studies have revealed the association of metabolic diseases with inflammation. Mitochondria are key organelles involved in metabolic regulation and important drivers of inflammation. However, it is uncertain whether the inhibition of mitochondrial protein translation results in the development of metabolic diseases, such that the metabolic benefits related to the inhibition of mitochondrial activity remain unclear. Mitochondrial methionyl-tRNA formyltransferase (Mtfmt) functions in the early stages of mitochondrial translation. In this study, we reveal that feeding with a high-fat diet led to the upregulation of Mtfmt in the livers of mice and that a negative correlation existed between hepatic Mtfmt gene expression and fasting blood glucose levels. A knockout mouse model of Mtfmt was generated to explore its possible role in metabolic diseases and its underlying molecular mechanisms. Homozygous knockout mice experienced embryonic lethality, but heterozygous knockout mice showed a global reduction in Mtfmt expression and activity. Moreover, heterozygous mice showed increased glucose tolerance and reduced inflammation, which effects were induced by the high-fat diet. The cellular assays showed that Mtfmt deficiency reduced mitochondrial activity and the production of mitochondrial reactive oxygen species and blunted nuclear factor-\u03baB activation, which, in turn, downregulated inflammation in macrophages. The results of this study indicate that targeting Mtfmt-mediated mitochondrial protein translation to regulate inflammation might provide a potential therapeutic strategy for metabolic diseases.<\/jats:p>","DOI":"10.3390\/ijms24065999","type":"journal-article","created":{"date-parts":[[2023,3,22]],"date-time":"2023-03-22T08:36:16Z","timestamp":1679474176000},"page":"5999","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Mitochondrial Methionyl-tRNA Formyltransferase Deficiency Alleviates Metaflammation by Modulating Mitochondrial Activity in Mice"],"prefix":"10.3390","volume":"24","author":[{"given":"Xiaoxiao","family":"Sun","sequence":"first","affiliation":[{"name":"Key Laboratory of Animal Physiology & Biochemistry, Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suyuan","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Physiology & Biochemistry, Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiangxue","family":"Cai","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Physiology & Biochemistry, Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miaoxin","family":"Yang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Physiology & Biochemistry, Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenxuan","family":"Li","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Physiology & Biochemistry, Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meiling","family":"Tan","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Physiology & Biochemistry, Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8019-8480","authenticated-orcid":false,"given":"Bin","family":"He","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Physiology & Biochemistry, Ministry of Agriculture and Rural Affairs, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China"},{"name":"MOE Joint International Research Laboratory of Animal Health & Food Safety, Nanjing Agricultural University, Nanjing 210095, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"440","DOI":"10.2337\/dci17-0005","article-title":"Diabetes and Aging: Unique Considerations and Goals of Care","volume":"40","author":"Kalyani","year":"2017","journal-title":"Diabetes Care"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2239","DOI":"10.1016\/S0140-6736(17)30058-2","article-title":"Type 2 diabetes","volume":"389","author":"Chatterjee","year":"2017","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1038\/nature05485","article-title":"Inflammation and metabolic disorders","volume":"444","author":"Hotamisligil","year":"2006","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.cmet.2010.12.008","article-title":"NF-kappaB, inflammation, and metabolic disease","volume":"13","author":"Baker","year":"2011","journal-title":"Cell Metab."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1101\/gad.346312.120","article-title":"Chronic tissue inflammation and metabolic disease","volume":"35","author":"Lee","year":"2021","journal-title":"Genes Dev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1038\/s41574-018-0059-4","article-title":"Inflammaging: A new immune-metabolic viewpoint for age-related diseases","volume":"14","author":"Franceschi","year":"2018","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1038\/nature21363","article-title":"Inflammation, metaflammation and immunometabolic disorders","volume":"542","author":"Hotamisligil","year":"2017","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e2103304118","DOI":"10.1073\/pnas.2103304118","article-title":"Soluble mannose receptor induces proinflammatory macrophage activation and metaflammation","volume":"118","author":"Embgenbroich","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1494","DOI":"10.1172\/JCI26498","article-title":"MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity","volume":"116","author":"Kanda","year":"2006","journal-title":"J. Clin. Investig."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"347","DOI":"10.2337\/db09-0016","article-title":"Depletion of liver Kupffer cells prevents the development of diet-induced hepatic steatosis and insulin resistance","volume":"59","author":"Huang","year":"2010","journal-title":"Diabetes"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1016\/j.molcel.2016.01.028","article-title":"The Mitochondrial Basis of Aging","volume":"61","author":"Sun","year":"2016","journal-title":"Mol. Cell"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1038\/nrendo.2011.138","article-title":"The role of mitochondria in insulin resistance and type 2 diabetes mellitus","volume":"8","author":"Szendroedi","year":"2011","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1016\/j.cell.2007.08.047","article-title":"Targeted deletion of AIF decreases mitochondrial oxidative phosphorylation and protects from obesity and diabetes","volume":"131","author":"Pospisilik","year":"2007","journal-title":"Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1016\/j.cmet.2018.01.018","article-title":"Proteome Imbalance of Mitochondrial Electron Transport Chain in Brown Adipocytes Leads to Metabolic Benefits","volume":"27","author":"Masand","year":"2018","journal-title":"Cell Metab."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"101674","DOI":"10.1016\/j.redox.2020.101674","article-title":"Mitochondrial electron transport chain: Oxidative phosphorylation, oxidant production, and methods of measurement","volume":"37","author":"Braganza","year":"2020","journal-title":"Redox Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1016\/j.cmet.2012.02.013","article-title":"Impaired insulin\/IGF1 signaling extends life span by promoting mitochondrial L-proline catabolism to induce a transient ROS signal","volume":"15","author":"Zarse","year":"2012","journal-title":"Cell Metab."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"288","DOI":"10.2203\/dose-response.13-035.Ristow","article-title":"Mitohormesis: Promoting Health and Lifespan by Increased Levels of Reactive Oxygen Species (ROS)","volume":"12","author":"Ristow","year":"2014","journal-title":"Dose Response"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e20201416","DOI":"10.1084\/jem.20201416","article-title":"Mitophagy-mediated adipose inflammation contributes to type 2 diabetes with hepatic insulin resistance","volume":"218","author":"He","year":"2021","journal-title":"J. Exp. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.cell.2020.08.009","article-title":"Targeting Mitochondria-Located circRNA SCAR Alleviates NASH via Reducing mROS Output","volume":"183","author":"Zhao","year":"2020","journal-title":"Cell"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1002\/dmrr.623","article-title":"Metformin delays the manifestation of diabetes and vascular dysfunction in Goto-Kakizaki rats by reduction of mitochondrial oxidative stress","volume":"22","author":"Rosen","year":"2006","journal-title":"Diabetes Metab. Res. Rev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1016\/j.bbagrm.2011.11.009","article-title":"Mechanism of protein biosynthesis in mammalian mitochondria","volume":"1819","author":"Christian","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.mcn.2012.08.013","article-title":"Mitochondrial diseases: Translation matters","volume":"55","author":"Pearce","year":"2013","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1016\/j.cmet.2011.07.010","article-title":"Mutations in MTFMT underlie a human disorder of formylation causing impaired mitochondrial translation","volume":"14","author":"Tucker","year":"2011","journal-title":"Cell Metab."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1002\/acn3.725","article-title":"Leigh syndrome caused by mutations in MTFMT is associated with a better prognosis","volume":"6","author":"Hayhurst","year":"2019","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e298","DOI":"10.1212\/NXG.0000000000000298","article-title":"Leigh syndrome followed by parkinsonism in an adult with homozygous c.626C>T mutation in MTFMT","volume":"4","author":"Hemelsoet","year":"2018","journal-title":"Neurol. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1007\/s10048-016-0506-0","article-title":"Identification and functional characterization of a novel MTFMT mutation associated with selective vulnerability of the visual pathway and a mild neurological phenotype","volume":"18","author":"Weraarpachai","year":"2017","journal-title":"Neurogenetics"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"897","DOI":"10.12659\/MSM.906269","article-title":"Insulin Resistance Is Associated with Interleukin 1beta (IL-1beta) in Non-Diabetic Hemodialysis Patients","volume":"24","author":"Bi","year":"2018","journal-title":"Med. Sci. Monit."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1038\/ng0398-231","article-title":"Mitochondrial transcription factor A is necessary for mtDNA maintenance and embryogenesis in mice","volume":"18","author":"Larsson","year":"1998","journal-title":"Nat. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1016\/S1097-2765(03)00088-1","article-title":"Failure to produce mitochondrial DNA results in embryonic lethality in Rnaseh1 null mice","volume":"11","author":"Cerritelli","year":"2003","journal-title":"Mol. Cell"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"9717","DOI":"10.1093\/nar\/gks774","article-title":"p32\/gC1qR is indispensable for fetal development and mitochondrial translation: Importance of its RNA-binding ability","volume":"40","author":"Yagi","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"10933","DOI":"10.1128\/MCB.24.24.10933-10940.2004","article-title":"The mitochondrial SDHD gene is required for early embryogenesis, and its partial deficiency results in persistent carotid body glomus cell activation with full responsiveness to hypoxia","volume":"24","author":"Piruat","year":"2004","journal-title":"Mol. Cell. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1128\/MCB.23.3.916-922.2003","article-title":"The absence of mitochondrial thioredoxin 2 causes massive apoptosis, exencephaly, and early embryonic lethality in homozygous mice","volume":"23","author":"Nonn","year":"2003","journal-title":"Mol. Cell. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1038\/s41598-017-18828-3","article-title":"Mice deficient in the Shmt2 gene have mitochondrial respiration defects and are embryonic lethal","volume":"8","author":"Tani","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_34","first-page":"4674","article-title":"Knockout of Tmem70 alters biogenesis of ATP synthase and leads to embryonal lethality in mice","volume":"25","author":"Vrbacky","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1038\/nature02517","article-title":"Premature ageing in mice expressing defective mitochondrial DNA polymerase","volume":"429","author":"Trifunovic","year":"2004","journal-title":"Nature"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1038\/440600a","article-title":"Mitochondrial disease: Powerhouse of disease","volume":"440","author":"Lane","year":"2006","journal-title":"Nature"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"233","DOI":"10.2337\/db21-0173","article-title":"GRP75 Regulates Mitochondrial-Supercomplex Turnover to Modulate Insulin Sensitivity","volume":"71","author":"Zhao","year":"2022","journal-title":"Diabetes"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1146\/annurev.nutr.012809.104747","article-title":"Physiological insights gained from gene expression analysis in obesity and diabetes","volume":"30","author":"Keller","year":"2010","journal-title":"Annu. Rev. Nutr."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"8466","DOI":"10.1073\/pnas.1032913100","article-title":"Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC1 and NRF1","volume":"100","author":"Patti","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1139\/h06-071","article-title":"Mitochondrial oxidative function and type 2 diabetes","volume":"31","author":"Rabol","year":"2006","journal-title":"Appl. Physiol. Nutr. Metab."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1126\/science.1104343","article-title":"Mitochondrial dysfunction and type 2 diabetes","volume":"307","author":"Lowell","year":"2005","journal-title":"Science"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1016\/j.bbrc.2006.09.029","article-title":"Respiratory chain dysfunction in skeletal muscle does not cause insulin resistance","volume":"350","author":"Wredenberg","year":"2006","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1016\/j.cmet.2012.10.016","article-title":"Adipose-specific deletion of TFAM increases mitochondrial oxidation and protects mice against obesity and insulin resistance","volume":"16","author":"Vernochet","year":"2012","journal-title":"Cell Metab."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e2105587","DOI":"10.1002\/advs.202105587","article-title":"Hepatic Suppression of Mitochondrial Complex II Assembly Drives Systemic Metabolic Benefits","volume":"9","author":"Wang","year":"2022","journal-title":"Adv. Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.immuni.2020.09.011","article-title":"Tetracycline Antibiotics Induce Host-Dependent Disease Tolerance to Infection","volume":"54","author":"Colaco","year":"2021","journal-title":"Immunity"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"11183","DOI":"10.1038\/s41598-020-68053-8","article-title":"MTFMT deficiency correlates with reduced mitochondrial integrity and enhanced host susceptibility to intracellular infection","volume":"10","author":"Seo","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.cell.2014.04.043","article-title":"Heme oxygenase-1 drives metaflammation and insulin resistance in mouse and man","volume":"158","author":"Jais","year":"2014","journal-title":"Cell"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1038\/s41419-020-03347-3","article-title":"DHA\/AA alleviates LPS-induced Kupffer cells pyroptosis via GPR120 interaction with NLRP3 to inhibit inflammasome complexes assembly","volume":"12","author":"Fan","year":"2021","journal-title":"Cell Death Dis."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1016\/j.intimp.2012.08.006","article-title":"Malabaricone C suppresses lipopolysaccharide-induced inflammatory responses via inhibiting ROS-mediated Akt\/IKK\/NF-kappaB signaling in murine macrophages","volume":"14","author":"Kang","year":"2012","journal-title":"Int. Immunopharmacol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/6\/5999\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:00:46Z","timestamp":1760122846000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/6\/5999"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,22]]},"references-count":49,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2023,3]]}},"alternative-id":["ijms24065999"],"URL":"https:\/\/doi.org\/10.3390\/ijms24065999","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,22]]}}}