Systemic Effects of mitoTEMPO upon Lipopolysaccharide Challenge Are Due to Its Antioxidant Part, While Local Effects in the Lung Are Due to Triphenylphosphonium

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.

Protective vs. Therapeutic Effects of Mitochondria-Targeted Antioxidant MitoTEMPO on Rat Sciatic Nerve Crush Injury: A Comprehensive Electrophysiological Analysis

“…Recent studies highlight the use of mitochondria-targeted antioxidants, such as Mi-toTEMPO, which typically utilize triphenylphosphonium for mitochondria targeting. The functional moiety of MitoTEMPO, acting as a trap for ROS, is delivered to mitochondria, where it can scavenge mitochondrial ROS and mitigate oxidative damage [26]. Furthermore, studies have shown that MitoTEMPO can modulate mitochondrial function and structure.…”

“…One such mitochondria-specific antioxidant is MitoTEMPO (2-(2,2,6,6tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl) triphenylphosphonium chloride) [25]. In the case of MitoTEMPO, triphenylphosphonium is the mitochondrial-targeting moiety, which selectively accumulates in mitochondria due to its unusually high membrane potential, whereas the rest of the molecule is the functional moiety [26].…”

Cellular ROS and Antioxidants: Physiological and Pathological Role

“…For instance, it has been shown that mitoTEMPO has a beneficial effect on the majority of organs due to its antioxidant part (TEMPO). Still, the beneficial impact on the lung is due to phosphonium, the positively charged transport part of mitoTEMPO [9]. This controversy in the action of antioxidants, which depends on different pathological settings, affected signaling pathways, and different body/cell compartments, is often called the pleiotropic effects of antioxidants.…”

Mitokondri hedefli bir antioksidan olan Mito-TEMPO’nun donmuş insan sperm parametrelerine etkisi

“…This combination makes a compound that works well to remove superoxide from the mitochondria. Mito-TEMPO is also expected to keep the quality of human spermatozoa that have been frozen and then thawed (27,28). Weidinger et al found that Mito TEMPO decreased the expression of nitric oxide synthase in the liver, as well as markers of liver and kidney damage (aspartate aminotransferase and alanine aminotransferase) (urea and creatinine) (27).…”