Mitochondria‐Targeted Antioxidants SkQ1 and MitoTEMPO Failed to Exert a Long‐Term Beneficial Effect in Murine Polymicrobial Sepsis

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.

Inhibition of mitophagy drives macrophage activation and antibacterial defense during sepsis

“…However, in macrophages, mROS production contributes to bacterial clearance and host defense (26,27). In addition, mROS scavenging with SkQ1 or MitoTEMPOL in CLP-mediated polymicrobial infection in mice significantly reduced survival (55). Our data demonstrating that LPS/IFN-γ-mediated inhibition of mitophagy in macrophages led to enhanced mROS production and triggered the activation of macrophages are in line with these observations.…”

Targeting breast cancer metabolism with a novel inhibitor of mitochondrial ATP synthesis

“…CADD522 significantly increased intracellular ROS production in both MCF7 and MDA-468 cells ( Figure 4A). However, cotreatment with N-acetyl-l-cysteine (NAC, 5 mM), a widely used antioxidant [57,58], diminished the CADD522increased intracellular ROS levels to below the level of the control ( Figure 4B). We further determined mitochondrial ROS levels in cells treated with CADD522 for 24 hr using MitoSox Red, a fluorescent dye relatively specific for superoxide.…”

“…Pre-treatment of tumor cells with NAC, a general ROS scavenger has been shown to provide protection against the cytotoxicity of intracellular oxidants [58,71]. It is known that NAC can inhibit apoptosis [57] induced by ROS.…”

Endothelin A and B Receptors: Potential Targets for Microcirculatory-Mitochondrial Therapy in Experimental Sepsis

“…All the animals received 1.5 mL kg -1 crystalloid solution 6 h later subcutaneously to maintain fluid balance (Ringerfundin®, B. Braun, Melsungen, Germany) and an analgesic agent (Buprenorphine, 15 µg kg -1 , Richter Pharma, Hungary). A standardized scoring system was used 6 and 22 h after sepsis induction to assess the health status of the animals and to characterize the progression of sepsis (Supplementary Digital Content - Figure 1, http://links.lww.com/SHK/A918) (15,16). Twenty-two hours after induction, the animals were anesthetized with an ip mixture of ketamine (45.7 mg kg -1 ) and xylazine (9.12 mg kg -1 ) to start the invasive hemodynamic monitoring.…”