SIRT3-SOD2-mROS-dependent autophagy in cadmium-induced hepatotoxicity and salvage by melatonin

Abstract

Cadmium is one of the most toxic metal compounds found in the environment. It is well established that Cd induces hepatotoxicity in humans and multiple animal models. Melatonin, a major secretory product of the pineal gland, has been reported to protect against Cd-induced hepatotoxicity. However, the mechanism behind this protection remains to be elucidated. We exposed HepG2 cells to different concentrations of cadmium chloride (2.5, 5, and 10 μM) for 12 h. We found that Cd induced mitochondrial-derived superoxide anion-dependent autophagic cell death. Specifically, Cd decreased SIRT3 protein expression and activity and promoted the acetylation of SOD2, superoxide dismutase 2, mitochondrial, thus decreasing its activity, a key enzyme involved in mitochondrial ROS production, although Cd did not disrupt the interaction between SIRT3 and SOD2. These effects were ameliorated by overexpression of SIRT3. However, a catalytic mutant of SIRT3 (SIRT3H248Y) lacking deacetylase activity lost the capacity to suppress Cd-induced autophagy. Notably, melatonin treatment enhanced the activity but not the expression of SIRT3, decreased the acetylation of SOD2, inhibited mitochondrial-derived O2•− production and suppressed the autophagy induced by 10 μM Cd. Moreover, 3-(1H-1,2,3-triazol-4-yl)pyridine, a confirmed selective SIRT3 inhibitor, blocked the melatonin-mediated suppression of autophagy by inhibiting SIRT3-SOD2 signaling. Importantly, melatonin suppressed Cd-induced autophagic cell death by enhancing SIRT3 activity in vivo. These results suggest that melatonin exerts a hepatoprotective effect on mitochondrial-derived O2•−-stimulated autophagic cell death that is dependent on the SIRT3/SOD2 pathway.

SIRT1/3 Activation by Resveratrol Attenuates Acute Kidney Injury in a Septic Rat Model

“…Genetic inference or genetic knockout of SIRT3 accelerates diet-induced obesity, type 2 diabetes, and nonalcoholic fatty liver disease [8]. SIRT3 activation can deacetylate its downstream target SOD2 (also termed manganese superoxide dismutase, Mn-SOD), leading to a reduction in oxygen free radicals in the mitochondria and other subcellular organelles [12, 13]. Interestingly, the relationship between the functions of nuclear SIRT1 and mitochondrial SIRT3 is coordinated during the hypoinflammatory phase of sepsis in THP1 human promonocytes [29].…”

“…Interestingly, SIRT1 activity is decreased in the liver, spleen, small bowel, and lung tissue in experimental sepsis models, and SIRT1 activation could improve the outcome of sepsis and ameliorate the associated inflammatory response [10, 11]. Besides SIRT1, another sirtuin, SIRT3, has also received considerable attention [12, 13]. Several reports indicate that SIRT3 is exclusively located in the mitochondria and acts as an antioxidative enzyme [12].…”

“…Besides SIRT1, another sirtuin, SIRT3, has also received considerable attention [12, 13]. Several reports indicate that SIRT3 is exclusively located in the mitochondria and acts as an antioxidative enzyme [12]. In a previous study, our group found that activation of SIRT1/3 improves vascular hyporeactivity in severe hemorrhagic shock by alleviation of mitochondrial damage [14].…”

Action of Melatonin on Severe Acute Liver Failure in Rats

“…The hepatoprotective effect of MLT was demonstrated by Pi et al [13] when they observed increased SIRT3 protein activity and SOD2 acetylation. These findings confirm the probable hepatoprotective role of melatonin in severe fulminant hepatitis, as evidenced by Korkmaz et al [14] in the fight against ROS and reactive nitrogen species (RNS).…”

The Protective Effect of Autophagy on DNA Damage in Mouse Spermatocyte-Derived Cells Exposed to 1800 MHz Radiofrequency Electromagnetic Fields

“…3A). P62 serves as a link between LC3 and ubiquitinated substrates and a reduction in the amount of p62 reflects an increase in autophagic degradation [28]. Immunoblot analysis showed that RF-EMFs treatment decreased the level of p62 (Fig.…”