Melatonin Improves Mitochondrial Function by Promoting MT1/SIRT1/PGC-1 Alpha-Dependent Mitochondrial Biogenesis in Cadmium-Induced Hepatotoxicity In Vitro

Abstract

Melatonin is an indolamine synthesized in the pineal gland that has a wide range of physiological functions, and it has been under clinical investigation for expanded applications. Increasing evidence demonstrates that melatonin can ameliorate cadmium-induced hepatotoxicity. However, the potentially protective effects of melatonin against cadmium-induced hepatotoxicity and the underlying mechanisms of this protection remain unclear. This study investigates the protective effects of melatonin pretreatment on cadmium-induced hepatotoxicity and elucidates the potential mechanism of melatonin-mediated protection. We exposed HepG2 cells to different concentrations of cadmium chloride (2.5, 5, and 10μM) for 12 h. We found that Cd stimulated cytotoxicity, disrupted the mitochondrial membrane potential, increased reactive oxygen species production, and decreased mitochondrial mass and mitochondrial DNA content. Consistent with this finding, Cd exposure was associated with decreased Sirtuin 1 (SIRT1) protein expression and activity, thus promoted acetylation of PGC-1 alpha, a key enzyme involved in mitochondrial biogenesis and function, although Cd did not disrupt the interaction between SIRT1 and PGC-1 alpha. However, all cadmium-induced mitochondrial oxidative injuries were efficiently attenuated by melatonin pretreatment. Moreover, Sirtinol and SIRT1 siRNA each blocked the melatonin-mediated elevation in mitochondrial function by inhibiting SIRT1/ PGC-1 alpha signaling. Luzindole, a melatonin receptor antagonist, was found to partially block the ability of melatonin to promote SIRT1/ PGC-1 alpha signaling. In summary, our results indicate that SIRT1 plays an essential role in the ability of moderate melatonin to stimulate PGC-1 alpha and improve mitochondrial biogenesis and function at least partially through melatonin receptors in cadmium-induced hepatotoxicity.

Melatonin ameliorates myocardial ischemia/reperfusion injury in type 1 diabetic rats by preserving mitochondrial function: role of AMPK-PGC-1α-SIRT3 signaling

“…Moreover, Guo et al . demonstrated that melatonin pretreatment suppressed cadmium-induced hepatotoxicity by enhancing mitochondrial biogenesis34. We also demonstrated that in a non-diabetic MI/R rat model, melatonin treatment significantly reduced cardiac damage by reducing mitochondrial oxidative stress32.…”

Melatonin Ameliorates Arsenite-Induced Neurotoxicity: Involvement of Autophagy and Mitochondria

“…Secondly, our study is the first to show the arsenite-induced reduction in PGC-1α levels, a transcriptional co-activator which controls mitochondrial biosynthesis [48][49][50]. Previous studies have reported that melatonin improved mitochondrial function by promoting PGC-1α-dependent mitochondrial biogenesis in hepatocytes [51] and skeletal muscle cells [52]. Accordingly, melatonin may maintain mitochondrial mass by increasing PGC-1 levels in arsenite-treated primary cultured cortical neurons.…”

Caloric restriction, resveratrol and melatonin: Role of SIRT1 and implications for aging and related-diseases

“…In addition, in cadmium-induced hepatotoxicity, melatonin exerts positive effects, which are associated with enhanced mitochondrial biogenesis through a SIRT1-dependent PGC-1␣ pathway. This effect appeared to be mediated partially through the binding of melatonin to its MT1 recepor, which activates signaling to mitochondria (Guo et al, 2014).…”