Abstract
BackgroundLow concentrations of carbon monoxide (CO) protect hepatocytes against apoptosis and confers cytoprotection in several models of liver. Mitochondria are key organelles in cell death control via their membrane permeabilization and the release of pro-apoptotic factors.ResultsHerein, we show that CO prevents mitochondrial membrane permeabilization (MMP) in liver isolated mitochondria. Direct and indirect approaches were used to evaluate MMP inhibition by CO: mitochondrial swelling, mitochondrial depolarization and inner membrane permeabilization. Additionally, CO increases mitochondrial reactive oxygen species (ROS) generation, and their scavenging, by ß-carotene addition, decreases CO protection, which reveals the key role of ROS. Interestingly, cytochrome c oxidase transiently responds to low concentrations of CO by decreasing its activity in the first 5 min, later on there is an increase of cytochrome c oxidase activity, which were detected up to 30 min.ConclusionCO directly prevents mitochondrial membrane permeabilization, which might be implicated in the hepatic apoptosis inhibition by this gaseoustransmitter.
Highlights
Low concentrations of carbon monoxide (CO) protect hepatocytes against apoptosis and confers cytoprotection in several models of liver
Based on the following facts: (i) CO is an anti-apoptotic molecule in several hepatic models, hepatocytes and/ or liver and (ii) mitochondria are central executers of cell death process, via the mitochondrial membrane permeabilization (MMP); we explored the direct effect of CO into isolated liver mitochondria (MMP modulation) and the involvement of reactive oxygen species (ROS) in this process
Assessment of CO toxicity and establishment of optimal CO concentration in isolated liver mitochondria In order to evaluate the toxicity of carbon monoxide (CO) on isolated liver mitochondria, swelling and depolarization assays were performed with different doses of CO (10 to 500 μM)
Summary
Low concentrations of carbon monoxide (CO) protect hepatocytes against apoptosis and confers cytoprotection in several models of liver. Carbon monoxide (CO) is usually considered a harmful and toxic molecule due to its high affinity to heme proteins. Recent evidences show that low doses of CO can be cytoprotective, presenting several biological properties, namely, anti-apoptosis, anti-proliferation, anti-inflammation and vasodilatation [1]. In hepatocytes and/or liver models, CO appears to act as an anti-apoptotic molecule. By stimulating ATP production, CO activates p38 MAPK signalling, preventing apoptosis in human hepatocytes [3]. CO rescues mice from fulminant hepatitis, presenting a marked reduction of TNF-alpha-induced apoptosis [4] or via NO generation [5]. In primary cultures of rat hepatocytes, CO limits cytotoxicity induced by glucose deprivation through
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