Abstract
Mitochondria-targeted antioxidants (mtAOX) are a promising treatment strategy against reactive oxygen species-induced damage. Reports about harmful effects of mtAOX lead to the question of whether these could be caused by the carrier molecule triphenylphosphonium (TPP). The aim of this study was to investigate the biological effects of the mtAOX mitoTEMPO, and TPP in a rat model of systemic inflammatory response. The inflammatory response was induced by lipopolysaccharide (LPS) injection. We show that mitoTEMPO reduced expression of inducible nitric oxide synthase in the liver, lowered blood levels of tissue damage markers such as liver damage markers (aspartate aminotransferase and alanine aminotransferase), kidney damage markers (urea and creatinine), and the general organ damage marker, lactate dehydrogenase. In contrast, TPP slightly, but not significantly, increased the LPS-induced effects. Surprisingly, both mitoTEMPO and TPP reduced the wet/dry ratio in the lung after 24 h. In the isolated lung, both substances enhanced the increase in pulmonary arterial pressure induced by LPS observed within 3 h after LPS treatments but did not affect edema formation at this time. Our data suggest that beneficial effects of mitoTEMPO in organs are due to its antioxidant moiety (TEMPO), except for the lung where its effects are mediated by TPP.
Highlights
Understanding mechanisms that control intracellular signaling is an important but difficult task because signaling molecules, such as reactive oxygen species (ROS) are very short lived
We showed that incubation with LPS increases cytoplasmic ROS and both TPP and mitoTEMPO attenuate ROS levels (Supplementary Figure S1), suggesting that a part of cytoplasmic ROS is released from mitochondria
We show that the effects of TPP and mitoTEMPO differ in the lung from those elicited in the other organs
Summary
Understanding mechanisms that control intracellular signaling is an important but difficult task because signaling molecules, such as reactive oxygen species (ROS) are very short lived. Giant steps forward in understanding the role of mitochondrial ROS. This class of molecules has two components. In the majority of cases, triphenylphosphonium (TPP) acts as the mitochondria-targeting moiety. TPP is a hydrophobic, positively charged molecule that selectively accumulates in mitochondria due to their unusually high membrane potential [1]. The second part of the molecule, the functional moiety comprising different types of antioxidants, is delivered to mitochondria and serves as a trap for ROS
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