Protein Interaction Assessing Mitochondrial Biogenesis as a Next Generation Biomarker in Sepsis

Metabolic derangements in sepsis stem from mitochondrial injury and contribute to organ dysfunction and mortality. Thus, repair of mitochondrial damage seems pivotal for recovery and determining clinical outcome in sepsis. However, reliable biomarkers assessing mitochondrial repair noninvasively in...

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Published in:	CHEST critical care Vol. 2; no. 2; p. 100065
Main Authors:	Thon, Patrick, Trübner, Ellen, Zimmer, Frieda, Palmowski, Lars, Ehrentraut, Stefan F., Putensen, Christian, Henzler, Dietrich, Schwier, Elke, Witowski, Andrea, Marko, Britta, Ziehe, Dominik, Nowak, Hartmuth, Rump, Katharina, Bergmann, Lars, Wolf, Alexander, Unterberg, Matthias, Adamzik, Michael, Koos, Björn, Rahmel, Tim, Adamzik, Stephanie, Bazzi, Maha, von Busch, Alexander, Haberl, Helge, Rahmel, Barbara, Willemsen, Katrin, Zuelch, Birgit, Anft, Moritz, Babel, Nina, Annecke, Thorsten, Defosse, Jerome M., Limper, Ulrich, Wappler, Frank, Bode, Christian, Schewe, Jens-Christian, Bracht, Thilo, Sitek, Barbara, Eisennacher, Martin, Kleefisch, Daniel, Marcus, Katrin, Ellger, Björn, Oswald, Daniel, Ertmer, Christian, Zarbock, Alexander, Frey, Ulrich H., Fuchs, Katrin, Köhler, Thomas
Format:	Journal Article
Language:	English
Published:	Elsevier Inc 01-06-2024
Subjects:	mitochondrial biogenesis mitochondrial damage clearance mitochondrial transcription factor A protein interaction sepsis protein interaction PLA mtDNA mRNA NRF1 TFB2M mitochondrial biogenesis PBMC SOFA mitochondrial damage clearance TFAM mitochondrial transcription factor A sepsis MQC
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Summary:	Metabolic derangements in sepsis stem from mitochondrial injury and contribute to organ dysfunction and mortality. Thus, repair of mitochondrial damage seems pivotal for recovery and determining clinical outcome in sepsis. However, reliable biomarkers assessing mitochondrial repair noninvasively in peripheral blood are currently lacking. Are different gene transcripts related to mitochondrial repair (ie, biogenesis, fusion, fission, mitophagy) and the protein interaction assessing mitochondrial biogenesis, both measured in peripheral blood, associated with disease severity and clinical outcome? Healthy control patients (n = 22), uninfected critically ill control patients (n = 13), and patients with sepsis (n = 75) were included in this prospective multicentric observational study. Gene products of mitochondrial quality control and mitochondrial DNA were measured on day 1 and 4 in peripheral blood mononuclear cells. In addition, we assessed in the same samples the mitochondrial protein interaction of mitochondrial transcription factor A (TFAM)-mitochondrial transcription factor B2 (TFB2M) using a proximity ligation assay. Patients with sepsis were stratified in the outcome-related subgroups ICU-free within 1 week (n = 16), not ICU-free within 1 week (n = 36), and 30-day nonsurvivors (n = 23). Transcript levels of the assessed messenger RNA markers of patients with sepsis were not associated with disease severity nor did they predict clinical outcome. Strikingly, the mitochondrial protein interaction of TFAM-TFB2M on day 4 (P < .05) and the difference between day 1 and 4 (P < .001) allowed stratification in the three clinical outcome subgroups. In addition, a decline in TFAM-TFB2M protein interactions between day 1 and 4 was an independent predicator for 30-day mortality (adjusted hazard ratio, 8.34; 95% CI, 2.73-25.45; P < .001). Patients with sepsis with an early activation of mitochondrial biogenesis were more likely to be ICU-free within 1 week. A mitochondrial and clinical recovery can be assessed via the protein interaction of TFAM-TFB2M in peripheral blood. Thus, mitochondrial protein interactions targeting mitochondrial biogenesis provide a promising dimension of novel biomarkers assessing mitochondrial dysfunction in sepsis.
ISSN:	2949-7884 2949-7884
DOI:	10.1016/j.chstcc.2024.100065