Veres, Balázs and Erős, Krisztián and Antus, Csenge Petra and Kálmán, Nikoletta and Fónai, Fruzsina and Jakus, Péter and Boros, Éva and Hegedűs, Zoltán and Nagy, István and Tretter, László and Gallyas, Ferenc and Sümegi, Balázs (2021) Cyclophilin D-dependent mitochondrial permeability transition amplifies inflammatory reprogramming in endotoxemia. FEBS OPEN BIO, 11 (3). pp. 684-704. ISSN 2211-5463
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Abstract
Microorganisms or LPS (lipopolysaccharide), an outer membrane component of Gram-negative bacteria, can induce a systemic inflammatory response that leads to sepsis, multiple organ dysfunction, and mortality. Here, we investigated the role of cyclophilin D (CypD)-dependent mitochondrial permeability transition (mPT) in the immunosuppressive phase of LPS-induced endotoxic shock. The liver plays an important role in immunity and organ dysfunction; therefore, we used liver RNA sequencing (RNAseq) data, Ingenuity® Pathway Analysis (IPA ® ) to investigate the complex role of mPT formation in inflammatory reprogramming and disease progression. LPS induced significant changes in the expression of 2844 genes, affecting 179 pathways related to mitochondrial dysfunction, defective oxidative phosphorylation, nitric oxide (NO) and reactive oxygen species (ROS) accumulation, nuclear factor, erythroid 2 like 2 (Nrf2), Toll-like receptors (TLRs), and tumor necrosis factor α receptor (TNFR)-mediated processes in wild-type mice. The disruption of CypD reduced LPS-induced alterations in gene expression and pathways involving TNFRs and TLRs, in addition to improving survival and attenuating oxidative liver damage and the related NO- and ROS-producing pathways. CypD deficiency diminished the suppressive effect of LPS on mitochondrial function, nuclear- and mitochondrial-encoded genes, and mitochondrial DNA (mtDNA) quantity, which could be critical in improving survival. Our data propose that CypD-dependent mPT is an amplifier in inflammatory reprogramming and promotes disease progression. The mortality in human sepsis and shock is associated with mitochondrial dysfunction. Prevention of mPT by CypD disruption reduces inflammatory reprogramming, mitochondrial dysfunction, and lethality; therefore, CypD can be a novel drug target in endotoxic shock and related inflammatory diseases.
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| Additional Information: | Department of Biochemistry and Medical Chemistry, Medical School, University of Pecs, Hungary MTA-PTE Nuclear-Mitochondrial Interactions Research Group, Pecs, Hungary Szentagothai Janos Research Center, University of Pecs, Hungary Institute of Biochemistry, Biological Research Centre, Szeged, Hungary Institute of Biophysics, Biological Research Centre, Szeged, Hungary SeqOmics Biotechnology Ltd, Morahalom, Hungary Department of Medical Biochemistry, Semmelweis University, Budapest, Hungary Export Date: 30 April 2021 Correspondence Address: Veres, B.; Department of Biochemistry and Medical Chemistry, Hungary; email: balazs.veres@aok.pte.hu Funding details: Emberi Eroforrások Minisztériuma, EMMI Funding details: European Social Fund, ESF, A2‐ELMH‐12‐0082 Funding details: European Commission, EC Funding details: Magyar Tudományos Akadémia, MTA Funding text 1: We would like to dedicate this paper in memory of our honored and beloved professor Balazs Sumegi. This work was supported by GINOP‐2.3.2‐15‐2016‐00049 and GINOP‐2.3.2‐15‐2016‐00039 and GINOP‐2.3.3‐15‐2016‐00025. NK was funded by the ÚNKP‐17‐III‐3 New National Excellence Program of the Ministry of Human Capacities. ÉB was funded by the European Union and the State of Hungary, cofinanced by the European Social Fund in the framework of ‘National Excellence Program’ (grant number A2‐ELMH‐12‐0082); IN was supported by the János Bolyai Research Scholarship of the Hungarian Academy of Sciences. Department of Biochemistry and Medical Chemistry, Medical School, University of Pecs, Hungary MTA-PTE Nuclear-Mitochondrial Interactions Research Group, Pecs, Hungary Szentagothai Janos Research Center, University of Pecs, Hungary Institute of Biochemistry, Biological Research Centre, Szeged, Hungary Institute of Biophysics, Biological Research Centre, Szeged, Hungary SeqOmics Biotechnology Ltd, Morahalom, Hungary Department of Medical Biochemistry, Semmelweis University, Budapest, Hungary Export Date: 5 May 2021 Correspondence Address: Veres, B.; Department of Biochemistry and Medical Chemistry, Hungary; email: balazs.veres@aok.pte.hu Funding details: Emberi Eroforrások Minisztériuma, EMMI Funding details: European Social Fund, ESF, A2‐ELMH‐12‐0082 Funding details: European Commission, EC Funding details: Magyar Tudományos Akadémia, MTA Funding text 1: We would like to dedicate this paper in memory of our honored and beloved professor Balazs Sumegi. This work was supported by GINOP‐2.3.2‐15‐2016‐00049 and GINOP‐2.3.2‐15‐2016‐00039 and GINOP‐2.3.3‐15‐2016‐00025. NK was funded by the ÚNKP‐17‐III‐3 New National Excellence Program of the Ministry of Human Capacities. ÉB was funded by the European Union and the State of Hungary, cofinanced by the European Social Fund in the framework of ‘National Excellence Program’ (grant number A2‐ELMH‐12‐0082); IN was supported by the János Bolyai Research Scholarship of the Hungarian Academy of Sciences. Funding Agency and Grant Number: New National Excellence Program of the Ministry of Human Capacities [uNKP-17-III-3]; European UnionEuropean Commission; State of Hungary; European Social Fund in the framework of 'National Excellence Program' [A2-ELMH-12-0082]; Janos Bolyai Research Scholarship of the Hungarian Academy of SciencesHungarian Academy of Sciences; [GINOP-2.3.2-15-2016-00049]; [GINOP-2.3.2-15-2016-00039]; [GINOP-2.3.3-15-2016-00025] Funding text: We would like to dedicate this paper in memory of our honored and beloved professor Balazs Sumegi. This work was supported by GINOP-2.3.2-15-2016-00049 and GINOP-2.3.2-15-2016-00039 and GINOP-2.3.3-15-2016-00025. NK was funded by the uNKP-17-III-3 New National Excellence Program of the Ministry of Human Capacities. EB was funded by the European Union and the State of Hungary, cofinanced by the European Social Fund in the framework of 'National Excellence Program' (grant number A2-ELMH-12-0082); IN was supported by the Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences. Department of Biochemistry and Medical Chemistry, Medical School, University of Pecs, Hungary MTA-PTE Nuclear-Mitochondrial Interactions Research Group, Pecs, Hungary Szentagothai Janos Research Center, University of Pecs, Hungary Institute of Biochemistry, Biological Research Centre, Szeged, Hungary Institute of Biophysics, Biological Research Centre, Szeged, Hungary SeqOmics Biotechnology Ltd, Morahalom, Hungary Department of Medical Biochemistry, Semmelweis University, Budapest, Hungary Export Date: 20 September 2021 Correspondence Address: Veres, B.; Department of Biochemistry and Medical Chemistry, Hungary; email: balazs.veres@aok.pte.hu |
| Uncontrolled Keywords: | Inflammation; LIVER; ENDOTOXIN; ANTIOXIDANT; Mitochondria; Gene Expression; Toll-like receptor; Reprogramming; cyclophilin D; Oxidative stress; |
| Subjects: | Q Science / természettudomány > QH Natural history / természetrajz > QH301 Biology / biológia > QH3011 Biochemistry / biokémia Q Science / természettudomány > QH Natural history / természetrajz > QH301 Biology / biológia > QH3020 Biophysics / biofizika |
| SWORD Depositor: | MTMT SWORD |
| Depositing User: | MTMT SWORD |
| Date Deposited: | 07 Feb 2022 09:07 |
| Last Modified: | 07 Feb 2022 09:07 |
| URI: | http://real.mtak.hu/id/eprint/137474 |
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