A molecular mechanism for mimosine-induced apoptosis involving oxidative stress and mitochondrial activation

Abstract

Mimosine, a non-protein amino acid, is mainly known for its action as a reversible inhibitor of DNA replication and, therefore, has been widely used as a cell cycle synchronizing agent. Recently, it has been shown that mimosine also induces apoptosis, as mainly reflected in its ability to elicit characteristic nuclear changes. The present study elucidates the mechanism underlying mimosine's apoptotic effects, using the U-937 leukemia cell line. We now demonstrate that in isolated rat liver mitochondria, mimosine induces mitochondrial swelling that can be inhibited by cyclosporine A, indicative of permeability transition (PT) mega-channel opening. Mimosine-induced apoptosis was accompanied by formation of hydrogen peroxide and a decrease in reduced glutathione levels. The apoptotic process was partially inhibited by cyclosporine A and substantially blocked by the antioxidant N-acetylcysteine, suggesting an essential role for reactive oxygen species formation during the apoptotic processes. The apoptosis induced by mimosine was also accompanied by a decrease in mitochondrial membrane potential, cytochrome c release and caspase 3 and 9 activation. Our results thus imply that mimosine activates apoptosis through mitochondrial activation and formation of H2O2, both of which play functional roles in the induction of cell death.

Activation of the Prereplication Complex Is Blocked by Mimosine through Reactive Oxygen Species-activated Ataxia Telangiectasia Mutated (ATM) Protein without DNA Damage

“…For instance, ATM is activated in the absence of DNA damage in response to hypoxic stress (58,59). Mimosine is a hypoxia-mimetic agent, and mimosine treatment has been reported to increase the production of ROS, one of the hypoxia mediators (60,65,66). We show that the activation of ATM upon mimosine treatment is induced in response to ROS-mediated hypoxic stress (Fig.…”

Regulation of Autophagy by α1-Antitrypsin: “A Foe of a Foe Is a Friend”

“…This serpin is produced primarily by liver cells (70% to 80%), but it is also synthesized by monocytes, macrophages, pulmonary alveolar cells, and by intestinal and corneal epithelia (11). De novo synthesis of AAT also has been demonstrated in human cancer cells and strongly expressed AAT-positive cases have poor prognosis.…”

“…Cell cycle phase distribution treatment was analyzed by flow cytometry using propidium iodide (PI) (Sigma-Aldrich) staining (11). Control and treated cells were harvested by trypsin, washed with PBS, then fixed in 95% ethanol and stored at 4°C for up to 7 d before DNA analysis.…”

“…AAT, a major blood protein, inhibits neutrophil elastase, proteinase-3, cathepsin G, thrombin, trypsin and other proteinases (11). Of note, AAT was shown to protect islet cells from apoptotic death (12).…”

Humanin Derivatives Inhibit Necrotic Cell Death in Neurons

“…Mitochondria were isolated from the livers of Sprague-Dawley female rats (200-300 g) by differential centrifugation as described previously (31,32). The livers were homogenized in ice-cold mitochondria isolation buffer (250 mmol/L sucrose, 0.1 mmol/L EDTA, 1 μg/mL leupeptine, 0.15 μmol/L phenylmethanesulfonyl fluoride and 10 mmol/L HEPES/KOH, pH = 7.2), 3 mL/mg liver, by using an electric homogenizer at 1,000 rpm for 10 min.…”