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Published on: January 22, 2017
Mitochondria-Targeted Antioxidants SkQ1 and MitoTEMPO Failed to Exert a Long-Term Beneficial Effect in Murine
Pia Rademann1, Adelheid Weidinger1, Susanne Drechsler1
1Ludwig Boltzmann Institute for Experimental and Clinical Traumatology in the Trauma Research Center of AUVA, Vienna, Austria.
Abstract:
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 (5 nmol/kg), MitoTEMPO (50 nmol/kg), or vehicle 5 times post-CLP. Separately, 52 SkQ1-treated CLP mice were sacrificed at 24 h and 48 h 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 48 h post-CLP, dying mice had approximately 100-fold more CFUs in the spleen than survivors, but this was not SkQ1 related. At 48 h, macrophage and granulocyte counts increased in the peritoneal lavage but irrespectively of SkQ1. Similarly, hepatic mitophagy was not altered by SkQ1 at 24 h. 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.
Insights
Mitochondria-targeted antioxidants did not improve survival in polymicrobial sepsis models. SkQ1 even worsened mortality, suggesting limited long-term benefits for abdominal sepsis treatments.
Area of Science:
- Biomedical research
- Sepsis pathogenesis
- Mitochondrial dysfunction
Background:
- Mitochondrial reactive oxygen species (ROS) play a key role in sepsis.
- Mitochondria-targeted antioxidants (mtAOX) are potential therapeutic agents.
- Investigating mtAOX efficacy in polymicrobial sepsis is crucial.
Purpose of the Study:
- To evaluate the long-term effects of mtAOX (SkQ1, MitoTEMPO) on survival, inflammation, and organ homeostasis in murine sepsis.
- To determine if mtAOX can mitigate sepsis-induced organ damage and immune dysregulation.
- To explore the impact of mtAOX on bacterial load and immune cell response.
Main Methods:
- Polymicrobial sepsis induced by cecal ligation and puncture (CLP) in female CD-1 mice.
- Administration of SkQ1 or MitoTEMPO (mtAOX) or vehicle post-CLP.
- Assessment of 28-day mortality, circulating cytokines, organ function markers (urea, ALT, LDH, glucose), immune cell counts, and bacterial load.
Main Results:
- Neither SkQ1 nor MitoTEMPO improved long-term survival; SkQ1 increased mortality by 29%.
- Sepsis induced significant inflammation and organ dysfunction irrespective of mtAOX treatment.
- No significant differences in bacterial load, immune cell infiltration, or hepatic mitophagy were observed between mtAOX and vehicle groups.
Conclusions:
- Mitochondria-targeted antioxidants do not confer survival benefits in this polymicrobial abdominal sepsis model.
- The therapeutic window or specific sepsis model may influence mtAOX efficacy.
- Long-term outcomes of mtAOX in abdominal sepsis may differ from other sepsis models.
