Mitochondrion-targeted antioxidant SkQ1 prevents rapid animal death caused by highly diverse shocks

Abstract

The response to stress involves the activation of pathways leading either to protection from the stress origin, eventually resulting in development of stress resistance, or activation of the rapid death of the organism. Here we hypothesize that mitochondrial reactive oxygen species (mtROS) play a key role in stress-induced programmed death of the organism, which we called “phenoptosis” in 1997. We demonstrate that the synthetic mitochondria-targeted antioxidant SkQ1 (which specifically abolishes mtROS) prevents rapid death of mice caused by four mechanistically very different shocks: (a) bacterial lipopolysaccharide (LPS) shock, (b) shock in response to intravenous mitochondrial injection, (c) cold shock, and (d) toxic shock caused by the penetrating cation C12TPP. Importantly, under all these stresses mortality was associated with a strong elevation of the levels of pro-inflammatory cytokines and administration of SkQ1 was able to switch off the cytokine storms. Since the main effect of SkQ1 is the neutralization of mtROS, this study provides evidence for the role of mtROS in the activation of innate immune responses mediating stress-induced death of the organism. We propose that SkQ1 may be used clinically to support patients in critical conditions, such as septic shock, extensive trauma, cooling, and severe infection by bacteria or viruses.

Six Functions of Respiration: Isn’t It Time to Take Control over ROS Production in Mitochondria, and Aging Along with It?

“…Partial prevention of LPS-induced fatal shock by an MTA treatment was reported in 2019 by Zorov and colleagues [ 117 ], who applied SkQR1 to 7-day-old newborn rats. In our recent study [ 130 ], the pretreatment with SkQ1 almost completely prevented LPS-induced mortality in young mice ( Figure 4 A), while in old animals (in which LPS toxicity was more pronounced), the protective effect of SkQ1 was only partial. LPS shock is thought to be associated with the so-called “cytokine storm” when large amounts of pro-inflammatory cytokines are released into the bloodstream.…”

“…In the most recent study [ 130 ], we analyzed the effects of SkQ1 in four completely different mouse models of fatal shock caused by (1) bacterial lipopolysaccharide (LPS), (2) injection of mitochondria into the bloodstream, (3) short-term cooling of animals at −20 °C, and (4) lethal dose of mitochondria-targeted toxin. In the first three cases, the mice were completely saved from death, and in the last one, every second mouse survived ( Figure 4 ).…”

Role of Mitochondria in the Regulation of Effector Functions of Granulocytes

“…Notably, SkQ1 eye drops have shown high efficacy in various models of inflammatory eye diseases [ 171 , 172 ], as well as in a clinical study addressing dry eye syndrome [ 173 ]. More recently, SkQ1 has been shown to prevent rapid death in mice induced by four very different shocks induced by LPS, intravenous mitochondrial injection, cooling, and toxic doses of C 12 TPP [ 174 ]. It is important to note that all of these stresses were accompanied by a strong increase in the level of pro-inflammatory cytokines and that SkQ1 prevented this cytokine storm.…”

Mitochondria-Targeted Antioxidant Therapeutics for Traumatic Brain Injury

“…In the case of SkQ1, the phosphorus cation bound to three phenyl rings (TPP + ) is conjugated to plastoquinol via a decyl linker. The binding of this cation to the phenyls ensures the ability of SkQ1 to penetrate membranes [ 105 ]. A positive electrical charge leads to a thousand-fold accumulation of SkQ1 in the mitochondrial membrane’s inner layer [ 105 ].…”

“…The binding of this cation to the phenyls ensures the ability of SkQ1 to penetrate membranes [ 105 ]. A positive electrical charge leads to a thousand-fold accumulation of SkQ1 in the mitochondrial membrane’s inner layer [ 105 ]. SkQ1 is able to reduce cardiac ischemic injury, and is well known for lipid peroxidation inhibition [ 106 , 107 , 108 , 109 ].…”