Mitochondria-targeted antioxidants SkQ1 and MitoTEMPO failed to exert a long-term beneficial effect in murine polymicrobial sepsis

Pia Rademann, Adelheid Weidinger, Susanne Drechsler, Andras Meszaros, Johannes Zipperle, Mohammad Jafarmadar, Sergiu Dumitrescu, Ara Hacobian, Luisa Ungelenk, Franziska Röstel, J. Kaszaki, Andrea Szabo, Vladimir P. Skulachev, Michael Bauer, Soheyl Bahrami, Sebastian Weis, Andrey V. Kozlov, Marcin F. Osuchowski

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Mitochondrial-derived reactive oxygen species have been deemed an important contributor in sepsis pathogenesis. We investigated whether two mitochondria-targeted antioxidants (mtAOX; SkQ1 and MitoTEMPO) improved long-term outcome, lessened inflammation, and improved organ homeostasis in polymicrobial murine sepsis. 3-month-old female CD-1 mice (n = 90) underwent cecal ligation and puncture (CLP) and received SkQ1 (5nmol/kg), MitoTEMPO (50 nmol/kg), or vehicle 5 times post-CLP. Separately, 52 SkQ1-treated CLP mice were sacrificed at 24h and 48h for additional endpoints. Neither MitoTEMPO nor SkQ1 exerted any protracted survival benefit. Conversely, SkQ1 exacerbated 28-day mortality by 29%. CLP induced release of 10 circulating cytokines, increased urea, ALT, and LDH, and decreased glucose but irrespectively of treatment. Similar occurred for CLP-induced lymphopenia/neutrophilia and the NO blood release. At 48h post-CLP, dying mice had approximately 100-fold more CFUs in the spleen than survivors, but this was not SkQ1 related. At 48h, macrophage and granulocyte counts increased in the peritoneal lavage but irrespectively of SkQ1. Similarly, hepatic mitophagy was not altered by SkQ1 at 24h. The absence of survival benefit of mtAOX may be due to the extended treatment and/or a relatively moderate-risk-of-death CLP cohort. Long-term effect of mtAOX in abdominal sepsis appears different to sepsis/inflammation models arising from other body compartments.

Original languageEnglish
Article number6412682
JournalOxidative Medicine and Cellular Longevity
Volume2017
DOIs
Publication statusPublished - Sep 19 2017

Fingerprint

Mitochondria
Punctures
Ligation
Sepsis
Antioxidants
Macrophages
Urea
Reactive Oxygen Species
Blood
Cytokines
Mitochondrial Degradation
Glucose
Inflammation
Peritoneal Lavage
Lymphopenia
Survival
Licensure
MitoTEMPO
Granulocytes
Reproduction

ASJC Scopus subject areas

  • Biochemistry
  • Ageing
  • Cell Biology

Cite this

Rademann, P., Weidinger, A., Drechsler, S., Meszaros, A., Zipperle, J., Jafarmadar, M., ... Osuchowski, M. F. (2017). Mitochondria-targeted antioxidants SkQ1 and MitoTEMPO failed to exert a long-term beneficial effect in murine polymicrobial sepsis. Oxidative Medicine and Cellular Longevity, 2017, [6412682]. https://doi.org/10.1155/2017/6412682

Mitochondria-targeted antioxidants SkQ1 and MitoTEMPO failed to exert a long-term beneficial effect in murine polymicrobial sepsis. / Rademann, Pia; Weidinger, Adelheid; Drechsler, Susanne; Meszaros, Andras; Zipperle, Johannes; Jafarmadar, Mohammad; Dumitrescu, Sergiu; Hacobian, Ara; Ungelenk, Luisa; Röstel, Franziska; Kaszaki, J.; Szabo, Andrea; Skulachev, Vladimir P.; Bauer, Michael; Bahrami, Soheyl; Weis, Sebastian; Kozlov, Andrey V.; Osuchowski, Marcin F.

In: Oxidative Medicine and Cellular Longevity, Vol. 2017, 6412682, 19.09.2017.

Research output: Contribution to journalArticle

Rademann, P, Weidinger, A, Drechsler, S, Meszaros, A, Zipperle, J, Jafarmadar, M, Dumitrescu, S, Hacobian, A, Ungelenk, L, Röstel, F, Kaszaki, J, Szabo, A, Skulachev, VP, Bauer, M, Bahrami, S, Weis, S, Kozlov, AV & Osuchowski, MF 2017, 'Mitochondria-targeted antioxidants SkQ1 and MitoTEMPO failed to exert a long-term beneficial effect in murine polymicrobial sepsis', Oxidative Medicine and Cellular Longevity, vol. 2017, 6412682. https://doi.org/10.1155/2017/6412682
Rademann, Pia ; Weidinger, Adelheid ; Drechsler, Susanne ; Meszaros, Andras ; Zipperle, Johannes ; Jafarmadar, Mohammad ; Dumitrescu, Sergiu ; Hacobian, Ara ; Ungelenk, Luisa ; Röstel, Franziska ; Kaszaki, J. ; Szabo, Andrea ; Skulachev, Vladimir P. ; Bauer, Michael ; Bahrami, Soheyl ; Weis, Sebastian ; Kozlov, Andrey V. ; Osuchowski, Marcin F. / Mitochondria-targeted antioxidants SkQ1 and MitoTEMPO failed to exert a long-term beneficial effect in murine polymicrobial sepsis. In: Oxidative Medicine and Cellular Longevity. 2017 ; Vol. 2017.
@article{75dda0b04c424a1cab3045bed9895751,
title = "Mitochondria-targeted antioxidants SkQ1 and MitoTEMPO failed to exert a long-term beneficial effect in murine polymicrobial sepsis",
abstract = "This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Mitochondrial-derived reactive oxygen species have been deemed an important contributor in sepsis pathogenesis. We investigated whether two mitochondria-targeted antioxidants (mtAOX; SkQ1 and MitoTEMPO) improved long-term outcome, lessened inflammation, and improved organ homeostasis in polymicrobial murine sepsis. 3-month-old female CD-1 mice (n = 90) underwent cecal ligation and puncture (CLP) and received SkQ1 (5nmol/kg), MitoTEMPO (50 nmol/kg), or vehicle 5 times post-CLP. Separately, 52 SkQ1-treated CLP mice were sacrificed at 24h and 48h for additional endpoints. Neither MitoTEMPO nor SkQ1 exerted any protracted survival benefit. Conversely, SkQ1 exacerbated 28-day mortality by 29{\%}. CLP induced release of 10 circulating cytokines, increased urea, ALT, and LDH, and decreased glucose but irrespectively of treatment. Similar occurred for CLP-induced lymphopenia/neutrophilia and the NO blood release. At 48h post-CLP, dying mice had approximately 100-fold more CFUs in the spleen than survivors, but this was not SkQ1 related. At 48h, macrophage and granulocyte counts increased in the peritoneal lavage but irrespectively of SkQ1. Similarly, hepatic mitophagy was not altered by SkQ1 at 24h. The absence of survival benefit of mtAOX may be due to the extended treatment and/or a relatively moderate-risk-of-death CLP cohort. Long-term effect of mtAOX in abdominal sepsis appears different to sepsis/inflammation models arising from other body compartments.",
author = "Pia Rademann and Adelheid Weidinger and Susanne Drechsler and Andras Meszaros and Johannes Zipperle and Mohammad Jafarmadar and Sergiu Dumitrescu and Ara Hacobian and Luisa Ungelenk and Franziska R{\"o}stel and J. Kaszaki and Andrea Szabo and Skulachev, {Vladimir P.} and Michael Bauer and Soheyl Bahrami and Sebastian Weis and Kozlov, {Andrey V.} and Osuchowski, {Marcin F.}",
year = "2017",
month = "9",
day = "19",
doi = "10.1155/2017/6412682",
language = "English",
volume = "2017",
journal = "Oxidative Medicine and Cellular Longevity",
issn = "1942-0900",
publisher = "Hindawi Publishing Corporation",

}

TY - JOUR

T1 - Mitochondria-targeted antioxidants SkQ1 and MitoTEMPO failed to exert a long-term beneficial effect in murine polymicrobial sepsis

AU - Rademann, Pia

AU - Weidinger, Adelheid

AU - Drechsler, Susanne

AU - Meszaros, Andras

AU - Zipperle, Johannes

AU - Jafarmadar, Mohammad

AU - Dumitrescu, Sergiu

AU - Hacobian, Ara

AU - Ungelenk, Luisa

AU - Röstel, Franziska

AU - Kaszaki, J.

AU - Szabo, Andrea

AU - Skulachev, Vladimir P.

AU - Bauer, Michael

AU - Bahrami, Soheyl

AU - Weis, Sebastian

AU - Kozlov, Andrey V.

AU - Osuchowski, Marcin F.

PY - 2017/9/19

Y1 - 2017/9/19

N2 - This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Mitochondrial-derived reactive oxygen species have been deemed an important contributor in sepsis pathogenesis. We investigated whether two mitochondria-targeted antioxidants (mtAOX; SkQ1 and MitoTEMPO) improved long-term outcome, lessened inflammation, and improved organ homeostasis in polymicrobial murine sepsis. 3-month-old female CD-1 mice (n = 90) underwent cecal ligation and puncture (CLP) and received SkQ1 (5nmol/kg), MitoTEMPO (50 nmol/kg), or vehicle 5 times post-CLP. Separately, 52 SkQ1-treated CLP mice were sacrificed at 24h and 48h for additional endpoints. Neither MitoTEMPO nor SkQ1 exerted any protracted survival benefit. Conversely, SkQ1 exacerbated 28-day mortality by 29%. CLP induced release of 10 circulating cytokines, increased urea, ALT, and LDH, and decreased glucose but irrespectively of treatment. Similar occurred for CLP-induced lymphopenia/neutrophilia and the NO blood release. At 48h post-CLP, dying mice had approximately 100-fold more CFUs in the spleen than survivors, but this was not SkQ1 related. At 48h, macrophage and granulocyte counts increased in the peritoneal lavage but irrespectively of SkQ1. Similarly, hepatic mitophagy was not altered by SkQ1 at 24h. The absence of survival benefit of mtAOX may be due to the extended treatment and/or a relatively moderate-risk-of-death CLP cohort. Long-term effect of mtAOX in abdominal sepsis appears different to sepsis/inflammation models arising from other body compartments.

AB - This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Mitochondrial-derived reactive oxygen species have been deemed an important contributor in sepsis pathogenesis. We investigated whether two mitochondria-targeted antioxidants (mtAOX; SkQ1 and MitoTEMPO) improved long-term outcome, lessened inflammation, and improved organ homeostasis in polymicrobial murine sepsis. 3-month-old female CD-1 mice (n = 90) underwent cecal ligation and puncture (CLP) and received SkQ1 (5nmol/kg), MitoTEMPO (50 nmol/kg), or vehicle 5 times post-CLP. Separately, 52 SkQ1-treated CLP mice were sacrificed at 24h and 48h for additional endpoints. Neither MitoTEMPO nor SkQ1 exerted any protracted survival benefit. Conversely, SkQ1 exacerbated 28-day mortality by 29%. CLP induced release of 10 circulating cytokines, increased urea, ALT, and LDH, and decreased glucose but irrespectively of treatment. Similar occurred for CLP-induced lymphopenia/neutrophilia and the NO blood release. At 48h post-CLP, dying mice had approximately 100-fold more CFUs in the spleen than survivors, but this was not SkQ1 related. At 48h, macrophage and granulocyte counts increased in the peritoneal lavage but irrespectively of SkQ1. Similarly, hepatic mitophagy was not altered by SkQ1 at 24h. The absence of survival benefit of mtAOX may be due to the extended treatment and/or a relatively moderate-risk-of-death CLP cohort. Long-term effect of mtAOX in abdominal sepsis appears different to sepsis/inflammation models arising from other body compartments.

UR - http://www.scopus.com/inward/record.url?scp=85029943916&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85029943916&partnerID=8YFLogxK

U2 - 10.1155/2017/6412682

DO - 10.1155/2017/6412682

M3 - Article

C2 - 29104729

AN - SCOPUS:85029943916

VL - 2017

JO - Oxidative Medicine and Cellular Longevity

JF - Oxidative Medicine and Cellular Longevity

SN - 1942-0900

M1 - 6412682

ER -