Enhancement of high glucose‐induced PINK1 expression by melatonin stimulates neuronal cell survival: Involvement of MT₂/Akt/NF‐κB pathway

Abstract

Hyperglycemia is a representative hallmark and risk factor for diabetes mellitus (DM) and is closely linked to DM-associated neuronal cell death. Previous investigators reported on a genome-wide association study and showed relationships between DM and melatonin receptor (MT), highlighting the role of MT signaling by assessing melatonin in DM. However, the role of MT signaling in DM pathogenesis is unclear. Therefore, we investigated the role of mitophagy regulators in high glucose-induced neuronal cell death and the effect of melatonin against high glucose-induced mitophagy regulators in neuronal cells. In our results, high glucose significantly increased PTEN-induced putative kinase 1 (PINK1) and LC-3B expressions; as well it decreased cytochrome c oxidase subunit 4 expression and Mitotracker™ fluorescence intensity. Silencing of PINK1 induced mitochondrial reactive oxygen species (ROS) accumulation and mitochondrial membrane potential impairment, increased expressions of cleaved caspases, and increased the number of annexin V-positive cells. In addition, high glucose-stimulated melatonin receptor 1B (MTNR1B) mRNA and PINK1 expressions were reversed by ROS scavenger N-acetyl cysteine pretreatment. Upregulation of PINK1 expression in neuronal cells is suppressed by pretreatment with MT receptor-specific inhibitor 4-P-PDOT. We further showed melatonin stimulated Akt phosphorylation, which was followed by nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) phosphorylation and nuclear translocation. Silencing of PINK1 expression abolished melatonin-regulated mitochondrial ROS production, cleaved caspase-3 and caspase-9 expressions, and the number of annexin V-positive cells. In conclusion, we have demonstrated the melatonin stimulates PINK1 expression via an MT /Akt/NF-κB pathway, and such stimulation is important for the prevention of neuronal cell apoptosis under high glucose conditions.

Activation of melatonin receptor 2 but not melatonin receptor 1 mediates melatonin‐conferred cardioprotection against myocardial ischemia/reperfusion injury

“…Intracoronary melatonin boosts coronary blood flow and cardiac function in anesthetized pigs, and this effect could be abolished by an MT2 receptor‐specific inhibitor 4‐P‐PDOT . In another report, melatonin improved neuronal cell survival in response to high‐glucose insult through PINK1 activation and resultant preservation of mitochondrial function, the effect of which could be abolished by MT2 receptor‐specific inhibitor 4‐P‐PDOT . Such data comprising tissue‐ and isoform‐specific effects of melatonin receptors are constructive in the development of the tissue‐ or isoform‐specific MT2 pharmacological activators for treating diverse pathologies.…”

Melatonin activates Parkin translocation and rescues the impaired mitophagy activity of diabetic cardiomyopathy through Mst1 inhibition

“…Onphachanh and colleagues demonstrated that melatonin stimulates PINK1 expression via the MT2/Akt/NF-κB pathway, which is important for the prevention of neuronal cell injury under high glucose conditions. 37 Our previous study also demonstrated that melatonin alleviates cardiac remodelling and dysfunction in DCM. 38…”

Melatonin: new insights on its therapeutic properties in diabetic complications

“…Melatonin elevates the expression of nuclear factor erythroid 2related factor 2 (Nrf2) resulting in the up-regulation of the expression of phase II antioxidant/detoxifying enzymes such as heme oxygenase-1 (HO-1) decreasing oxidative stress and activation of nuclear factor-κB (NF-κB) cascade [158].The expression of PINK1 and microtubule-associated proteins 1A/1B light chain 3 B (LC-3 B), mitophagy markers, increased in neuronal cells following treatment with melatonin. Since silencing of PINK1 expression impairs melatonin-mediated reduction of mitochondrial ROS production and apoptotic marker activation, it is suggested that melatonin prevents neuronal cell apoptosis under high glucose conditions through stimulating PINK1 expression; this effect of melatonin has been demonstrated to be MT2 receptor dependent [159].…”

“…In hyperglycemia state, the persistent oxidative stress contributes to damage to the nuclear DNA and the mitochondrial genetic material [168]. Anti-apoptotic effects Antioxidant effects [159] Page 12 of 20 Pourhanifeh et al Diabetol Metab Syndr (2020) 12:30 Hyperglycemia leads to apoptosis in different types of cells in diabetic nephropathy, such as the proximal tubule epithelial cells [169]. It has been previously explained that the apoptosis occurs through activating numerous intracellular signaling pathway [170].…”