Protein interaction assessing mitochondrial biogenesis as a next generation biomarker in sepsis: a prospective cohort study

Background 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. Research Question Are different gene transcripts related to mitochondrial repair (i.e., biogenesis, fusion, fission, mitophagy) and the protein interaction assessing mitochondrial biogenesis, both measured in peripheral blood, associated with disease severity and clinical outcome? Study Design and Methods Healthy controls (n=22), uninfected critically ill control patients (n=13), and 75 sepsis patients 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 TFAM-TFB2M using a proximity ligation assay. Septic patients 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 non-survivors” (n=23). Results Transcript levels of the assessed mRNA markers of septic patients were not associated with disease severity nor did they predict clinical outcome. Strikingly, the mitochondrial protein interaction of TFAM-TFB2M on day 4 (p<0.05) as well as the difference between day 1 and 4 (p<0.001) allowed stratification in the three clinical outcome subgroups. In addition, a decline in TFAM-TFB2M protein interactions between day 1 and day 4 was an independent predicator for 30-day mortality (aHR: 8.34; 95% CI: 2.73 to 25.45, p<0.001). Interpretation Sepsis patients 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.