{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T15:58:22Z","timestamp":1753891102052,"version":"3.41.2"},"reference-count":36,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,5,16]],"date-time":"2025-05-16T00:00:00Z","timestamp":1747353600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Repair of mitochondrial damage seems pivotal for clinical recovery and determining outcome in patients with critical COVID-19. However, reliable biomarkers for non-invasively assessing mitochondrial repair in peripheral blood of critically ill COVID-19 patients are currently lacking. Accordingly, we sought to assess different surrogates of mitochondrial repair in peripheral blood and correlate these measurements with clinical outcome in patients with critical COVID-19.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In this prospective multicentric cohort study, 88 critically ill COVID-19 patients were enrolled across three German intensive care units. Gene products of mitochondrial quality control (MFN2, PINK, TFAM, TFB2M) and the mtDNA copy number were measured in peripheral blood mononuclear cells. Furthermore, the protein interactions between TFAM and TFB2M were quantified. Patients were stratified regarding 30-day mortality. <\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Transcript levels of the assessed mRNA markers of mitochondrial quality\u00a0control were not associated with clinical outcome. In contrast, more than 10.7 protein interactions per cell were associated with a 74% 30-day survival (37 out of 50), while 10.7 or fewer protein interactions per cell were associated with a 32% 30-day survival (12 out of 38; p &amp;lt; 0.001). Furthermore, multivariable Cox regression analysis revealed TFAM-TFB2M protein interaction as an independent predictor for 30-day survival (HR: 3.2; 95% CI: 1.6 to 6.5; p &amp;lt; 0.001). <\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Our findings indicate that TFAM-TFB2M protein interactions, identified as a novel biomarker, are strongly and independently associated with 30-day survival in critical COVID-19. Therefore, our data suggest a significant impact of mitochondrial repair and quality control on clinical outcome in critical COVID-19. <\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1445403","type":"journal-article","created":{"date-parts":[[2025,5,16]],"date-time":"2025-05-16T05:22:25Z","timestamp":1747372945000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["The protein interaction of mitochondrial transcription factors A and B2 is associated with 30-day survival in critical COVID-19"],"prefix":"10.3389","volume":"16","author":[{"given":"Britta","family":"Westhus","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick","family":"Thon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lars","family":"Palmowski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katharina","family":"Rump","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bj\u00f6rn","family":"Koos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frederik","family":"Wiebel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Birte","family":"Dyck","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin","family":"Eisenacher","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Barbara","family":"Sitek","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie","family":"Pfaender","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nina","family":"Babel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Moritz","family":"Anft","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian","family":"Putensen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefan Felix","family":"Ehrentraut","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christina","family":"Weisheit","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander","family":"Zarbock","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thilo","family":"von Groote","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Witowski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthias","family":"Unterberg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hartmuth","family":"Nowak","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander","family":"Wolf","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lars","family":"Bergmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Adamzik","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dominik","family":"Ziehe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tim","family":"Rahmel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,5,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)30566-3","article-title":"Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study","volume":"395","author":"Zhou","year":"2020","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1016\/S0140-6736(20)30183-5","article-title":"Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China","volume":"395","author":"Huang","year":"2020","journal-title":"Lancet"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-0968-3","article-title":"Extrapulmonary manifestations of COVID-19","volume":"26","author":"Gupta","year":"2020","journal-title":"Nat Med"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0003686","article-title":"Dysregulation of mitochondrial dynamics and the muscle transcriptome in ICU patients suffering from sepsis induced multiple organ failure","volume":"3","author":"Fredriksson","year":"2008","journal-title":"PloS One"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.14670\/HH-18-354","article-title":"The kidnapping of mitochondrial function associated with the SARS-CoV-2 infection","volume":"36","author":"Soria-Castro","year":"2021","journal-title":"Histol Histopathol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3390\/cells11192969","article-title":"NSP4 and ORF9b of SARS-coV-2 induce pro-inflammatory mitochondrial DNA release in inner membrane-derived vesicles","volume":"11","author":"Faizan","year":"2022","journal-title":"Cells"},{"key":"B7","doi-asserted-by":"publisher","first-page":"102213","DOI":"10.1016\/j.rpth.2023.102213","article-title":"Platelets of COVID-19 patients display mitochondrial dysfunction, oxidative stress, and energy metabolism failure compatible with cell death","volume":"7","author":"Leopold","year":"2023","journal-title":"Res Pract Thromb Haemost"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.799896","article-title":"Mitochondrial dysfunction associates with acute T lymphocytopenia and impaired functionality in COVID-19 patients","volume":"12","author":"Mo","year":"2021","journal-title":"Front Immunol"},{"key":"B9","doi-asserted-by":"crossref","first-page":"103722","DOI":"10.1016\/j.isci.2021.103722","article-title":"SARS-CoV-2 infection enhances mitochondrial PTP complex activity to perturb cardiac energetics","volume":"25","author":"Ramachandran","year":"2022","journal-title":"iScience"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2021.780768","article-title":"SARS-coV-2 causes mitochondrial dysfunction and mitophagy impairment","volume":"12","author":"Shang","year":"2021","journal-title":"Front Microbiol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-031-28012-2_11","article-title":"Potential biomarkers of mitochondrial dysfunction associated with COVID-19 infection","volume":"1412","author":"Turton","year":"2023","journal-title":"Adv Exp Med Biol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2021.754708","article-title":"Peripheral blood mitochondrial DNA levels were modulated by SARS-coV-2 infection severity and its lessening was associated with mortality among hospitalized patients with COVID-19","volume":"11","author":"Valdes-Aguayo","year":"2021","journal-title":"Front Cell Infect Microbiol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2023.1228275","article-title":"Host mitochondria: more than an organelle in SARS-CoV-2 infection","volume":"13","author":"Shoraka","year":"2023","journal-title":"Front Cell Infect Microbiol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.143299","article-title":"Circulating mitochondrial DNA is an early indicator of severe illness and mortality from COVID-19","volume":"6","author":"Scozzi","year":"2021","journal-title":"JCI Insight"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1097\/CCM.0000000000003681","article-title":"Peripheral blood mononuclear cells demonstrate mitochondrial damage clearance during sepsis","volume":"47","author":"Kraft","year":"2019","journal-title":"Crit Care Med"},{"key":"B16","doi-asserted-by":"publisher","first-page":"21029","DOI":"10.1038\/s41598-020-78195-4","article-title":"Mitochondrial dysfunction in sepsis is associated with diminished intramitochondrial TFAM despite its increased cellular expression","volume":"10","author":"Rahmel","year":"2020","journal-title":"Sci Rep"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagrm.2012.03.002","article-title":"Mitochondrial transcription factor A regulates mitochondrial transcription initiation, DNA packaging, and genome copy number","volume":"1819","author":"Campbell","year":"2012","journal-title":"Biochim Biophys Acta"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2010.10.008","article-title":"Human mitochondrial transcription factor A is required for the segregation of mitochondrial DNA in cultured cells","volume":"317","author":"Kasashima","year":"2011","journal-title":"Exp Cell Res"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.chstcc.2024.100065","article-title":"Protein interaction assessing mitochondrial biogenesis as a next generation biomarker in sepsis: A prospective cohort study","volume":"2","author":"Thon","year":"2024","journal-title":"CHEST Crit Care"},{"key":"B20","doi-asserted-by":"publisher","first-page":"374","DOI":"10.1186\/s13054-019-2663-7","article-title":"The SOFA score-development, utility and challenges of accurate assessment in clinical trials","volume":"23","author":"Lambden","year":"2019","journal-title":"Crit Care"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3390\/jcm11237161","article-title":"Peak Plasma Levels of mtDNA Serve as a Predictive Biomarker for COVID-19 in-Hospital Mortality","volume":"11","author":"Edinger","year":"2022","journal-title":"J Clin Med"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00128.2022","article-title":"Absolute quantification of plasma mitochondrial DNA by droplet digital PCR marks COVID-19 severity over time during intensive care unit admissions","volume":"323","author":"Hepokoski","year":"2022","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1186\/s12882-018-1178-9","article-title":"Urinary mitochondrial DNA level as a biomarker of tissue injury in non-diabetic chronic kidney diseases","volume":"19","author":"Wei","year":"2018","journal-title":"BMC Nephrol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2020009063","article-title":"Circulating mitochondrial DNA is a proinflammatory DAMP in sickle cell disease","volume":"137","author":"Tumburu","year":"2021","journal-title":"Blood"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-006-9046-y","article-title":"Upregulation of mitochondrial gene expression in PBMC from convalescent SARS patients","volume":"26","author":"Shao","year":"2006","journal-title":"J Clin Immunol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.946731","article-title":"SARS-coV-2 achieves immune escape by destroying mitochondrial quality: comprehensive analysis of the cellular landscapes of lung and blood specimens from patients with COVID-19","volume":"13","author":"Duan","year":"2022","journal-title":"Front Immunol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2023.1256042","article-title":"Comparison of plasma mitochondrial DNA copy number in asymptomatic and symptomatic COVID-19 patients","volume":"14","author":"Shoraka","year":"2023","journal-title":"Front Microbiol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(02)09459-X","article-title":"Association between mitochondrial dysfunction and severity and outcome of septic shock","volume":"360","author":"Brealey","year":"2002","journal-title":"Lancet"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201003-0326OC","article-title":"Survival in critical illness is associated with early activation of mitochondrial biogenesis","volume":"182","author":"Carre","year":"2010","journal-title":"Am J Respir Crit Care Med"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00218.2006","article-title":"Derangements in mitochondrial metabolism in intercostal and leg muscle of critically ill patients with sepsis-induced multiple organ failure","volume":"291","author":"Fredriksson","year":"2006","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1002\/ana.26318","article-title":"COVID-19-associated critical illness myopathy with direct viral effects","volume":"91","author":"Dodig","year":"2022","journal-title":"Ann Neurol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2013.12.026","article-title":"A review of the mitochondrial and glycolytic metabolism in human platelets and leukocytes: implications for their use as bioenergetic biomarkers","volume":"2","author":"Kramer","year":"2014","journal-title":"Redox Biol"},{"key":"B33","doi-asserted-by":"publisher","first-page":"308","DOI":"10.1038\/s41392-021-00726-w","article-title":"HIF-1alpha promotes SARS-CoV-2 infection and aggravates inflammatory responses to COVID-19","volume":"6","author":"Tian","year":"2021","journal-title":"Signal Transduct Target Ther"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines10071746","article-title":"In vivo and ex vivo mitochondrial function in COVID-19 patients on the intensive care unit","volume":"10","author":"Streng","year":"2022","journal-title":"Biomedicines"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1007\/82_2013_334","article-title":"Analysis of protein interactions in situ by proximity ligation assays","volume":"377","author":"Koos","year":"2014","journal-title":"Curr Top Microbiol Immunol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.4161\/trns.2.2.14296","article-title":"The core human mitochondrial transcription initiation complex: It only takes two to tango","volume":"2","author":"Shutt","year":"2011","journal-title":"Transcription"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1445403\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,2]],"date-time":"2025-06-02T13:37:28Z","timestamp":1748871448000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1445403\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,16]]},"references-count":36,"alternative-id":["10.3389\/fimmu.2025.1445403"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1445403","relation":{},"ISSN":["1664-3224"],"issn-type":[{"type":"electronic","value":"1664-3224"}],"subject":[],"published":{"date-parts":[[2025,5,16]]},"article-number":"1445403"}}