Mitochondrial dysfunction in sepsis is associated with diminished intramitochondrial TFAM despite its increased cellular expression
- Sepsis is characterized by a dysregulated immune response, metabolic derangements and bioenergetic failure. These alterations are closely associated with a profound and persisting mitochondrial dysfunction. This however occurs despite increased expression of the nuclear-encoded transcription factor A (TFAM) that normally supports mitochondrial biogenesis and functional recovery. Since this paradox may relate to an altered intracellular distribution of TFAM in sepsis, we tested the hypothesis that enhanced extramitochondrial TFAM expression does not translate into increased intramitochondrial TFAM abundance. Accordingly, we prospectively analyzed PBMCs both from septic patients (n = 10) and lipopolysaccharide stimulated PBMCs from healthy volunteers (n = 20). Extramitochondrial TFAM protein expression in sepsis patients was 1.8-fold greater compared to controls (p = 0.001), whereas intramitochondrial TFAM abundance was approximate 80% less (p < 0.001). This was accompanied by lower mitochondrial DNA copy numbers (p < 0.001), mtND1 expression (p < 0.001) and cellular ATP content (p < 0.001) in sepsis patients. These findings were mirrored in lipopolysaccharide stimulated PBMCs taken from healthy volunteers. Furthermore, TFAM-TFB2M protein interaction within the human mitochondrial core transcription initiation complex, was 74% lower in septic patients (p < 0.001). In conclusion, our findings, which demonstrate a diminished mitochondrial TFAM abundance in sepsis and endotoxemia, may help to explain the paradox of lacking bioenergetic recovery despite enhanced TFAM expression.
Author: | Tim RahmelORCiDGND, Britta MarkoGND, Hartmuth Sebastian Burkhard NowakORCiDGND, Lars BergmannORCiDGND, Patrick ThonGND, Katharina RumpORCiDGND, Sebastian KreimendahlORCiDGND, Joachim RassowORCiDGND, Jürgen PetersGND, Mervyn SingerGND, Michael AdamzikORCiDGND, Björn KoosORCiDGND |
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URN: | urn:nbn:de:hbz:294-81332 |
DOI: | https://doi.org/10.1038/s41598-020-78195-4 |
Parent Title (English): | Scientific reports |
Publisher: | Springer Nature |
Place of publication: | Berlin |
Document Type: | Article |
Language: | English |
Date of Publication (online): | 2021/06/09 |
Date of first Publication: | 2020/12/03 |
Publishing Institution: | Ruhr-Universität Bochum, Universitätsbibliothek |
Tag: | Open Access Fonds Acute inflammation; Infectious diseases; Sepsis |
Volume: | 10 |
Issue: | Artikel 21029 |
First Page: | 21029-1 |
Last Page: | 21029-11 |
Note: | Article Processing Charge funded by the Deutsche Forschungsgemeinschaft (DFG) and the Open Access Publication Fund of Ruhr-Universität Bochum. |
Institutes/Facilities: | Institut für Biochemie und Pathobiochemie, Abteilung Zellbiochemie |
Knappschaftskrankenhaus Bochum, Klinik für Anästhesiologie, Intensivmedizin und Schmerztherapie | |
Dewey Decimal Classification: | Technik, Medizin, angewandte Wissenschaften / Medizin, Gesundheit |
open_access (DINI-Set): | open_access |
Licence (English): | Creative Commons - CC BY 4.0 - Attribution 4.0 International |