Westhus Britta, Thon Patrick, Palmowski Lars, Rump Katharina, Koos Björn, Wiebel Frederik, Dyck Birte, Eisenacher Martin, Sitek Barbara, Pfaender Stephanie, Babel Nina, Anft Moritz, Putensen Christian, Ehrentraut Stefan Felix, Weisheit Christina, Zarbock Alexander, von Groote Thilo, Witowski Andrea, Unterberg Matthias, Nowak Hartmuth, Wolf Alexander, Bergmann Lars, Adamzik Michael, Ziehe Dominik, Rahmel Tim
Klinik für Anästhesiologie, Intensivmedizin und Schmerztherapie, Universitätsklinikum Knappschaftskrankenhaus Bochum, Bochum, Germany.
Medical Proteome Analysis, Center for Proteindiagnostics (PRODI), Ruhr-University Bochum, Bochum, Germany.
Front Immunol. 2025 May 16;16:1445403. doi: 10.3389/fimmu.2025.1445403. eCollection 2025.
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.
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.
Transcript levels of the assessed mRNA markers of mitochondrial quality control 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 < 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 < 0.001).
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.
线粒体损伤的修复似乎对重症新型冠状病毒肺炎（COVID-19）患者的临床康复和预后判定至关重要。然而，目前缺乏用于非侵入性评估重症COVID-19患者外周血中线粒体修复的可靠生物标志物。因此，我们试图评估外周血中线粒体修复的不同替代指标，并将这些测量结果与重症COVID-19患者的临床结局相关联。
在这项前瞻性多中心队列研究中，德国三个重症监护病房纳入了88例重症COVID-19患者。检测外周血单个核细胞中线粒体质量控制的基因产物（MFN2、PINK、TFAM、TFB2M）以及线粒体DNA（mtDNA）拷贝数。此外，对TFAM和TFB2M之间的蛋白质相互作用进行定量分析。根据30天死亡率对患者进行分层。
所评估的线粒体质量控制mRNA标志物的转录水平与临床结局无关。相反，每个细胞超过10.7次蛋白质相互作用与30天生存率74%相关（50例中的37例），而每个细胞10.7次或更少的蛋白质相互作用与30天生存率32%相关（38例中的12例；p<0.001）。此外，多变量Cox回归分析显示TFAM-TFB2M蛋白质相互作用是30天生存的独立预测因素（风险比：3.2；95%置信区间：1.6至6.5；p<0.001）。
我们的研究结果表明，作为一种新型生物标志物的TFAM-TFB2M蛋白质相互作用与重症COVID-19患者的30天生存密切且独立相关。因此，我们的数据表明线粒体修复和质量控制对重症COVID-19患者的临床结局有显著影响。
