Manganese‐induced rat pheochromocytoma (PC12) cell death is independent of caspase activation

Abstract

Manganese (Mn) is an essential mineral that at high concentrations can produce an irreversible syndrome resembling Parkinson's disease. To examine the mechanism by which Mn elicits its toxic response, we have selected the rat pheochromocytoma cells (PC12) as our model system because it possesses much of the biochemical machinery associated with dopaminergic neurons. Mn-induced PC12 cell death is both time and concentration dependent with approximately 50% cell survival at 48 hr in the presence of 0.3 mM Mn. To determine whether oxidative stress contributed to cytotoxicity induced by Mn, lipid peroxidation was assessed in Mn-treated in PC12 cells. The highly sensitive HPLC assay that measures the lipid peroxide product, 9-HODE, was used and results of these experiments demonstrate there was no increase in the lipid peroxidation in cells exposed to 0.3 mM Mn for 24 hr. Mn was found to stimulate the activation of the apoptotic marker proteins, p38 and caspase-3 within the first 24 hr of treatment. The selective inhibitor of caspase-3, DEVD-CHO, and the nonselective caspase inhibitor, Z-VAD-FMK, however, fail to prevent Mn-induced PC12 cell death. Studies were performed to determine the role of mitochondria in initiating or supporting Mn cytotoxicity, because Mn has been reported to cause changes in membrane permeability. Mn caused a decrease in ATP levels in PC12 cells in both a time and concentration dependent manner. We hypothesize that both apoptosis and necrosis contribute to PC12 cell death although the necrotic events prevail even when the apoptotic signaling is inhibited.

Overexpression of miR‐138‐5p suppresses MnCl2‐induced autophagy by targeting SIRT1 in SH‐SY5Y cells

“…Mn exposure has been also shown to cause neurotoxicity in vitro and in vivo . Excessive Mn induces oxidative stress in the brain to exacerbate mitochondrial dysfunction and stimulates ER stress‐mediated apoptosis in rat striatum neurocytes . In previous research, we also found Mn can induce mitochondrial dysfunction in SH‐SY5Y cells .…”

Systematic literature review on Parkinson's disease and Childhood Leukaemia and mode of actions for pesticides

“…2008; Zhang et al, 2007). However, apoptosis-independent cell death has also been observed in one study, suggesting that apoptosis is not the only cell death mechanism triggered by Mn (Roth et al, 2000).…”

“…Apoptotic cell death is the most-reported key downstream event regarding Mn-induced neurotoxicity (Chun et al, 2001b;Desole et al, 1996;Desole et al, 1997;Hirata et al, 1998;Latchoumycandane et al, 2005;Malecki, 2001;Roth et al, 2000;Xu et al, 2014). The activation of apoptosis as well as increased oxidative stress in microglia appeared to be dependent on the activation (via phosphorylation) of MAP kinases JNK and ERK (Bae et al, 2006;Hirata et al, 1998;Yin et al, Supporting publications 2016: EN-955 76 The present document has been produced and adopted by the bodies identified above as authors.…”

“…It has been reported that Mn enters the mitochondria via a mitochondrial Ca 2+ uniporter (Gavin et al, 1999). Some of the mitochondrial dysfunction include altered mitochondrial respiration (Gavin et al, 1999), inhibition of mitochondrial aconitase activity (Zheng et al, 1998), loss of mitochondrial transmembrane potential (Malecki, 2001;Rao & Norenberg, 2004;Yin et al, 2008) and reduction of ATP (Milatovic et al, 2009;Roth et al, 2000). Inhibition of the mitochondrial electron transport chain by Mn (e.g.…”

Effects of dietary protein and calcium on thymus apoptosis induced by fluoride in female rats (Wistar rats)

“…Caspases are cysteine proteases that cleave a critical set of cellular Pr to initiate the apoptotic signal including several representatives involved in apoptosis (Roth et al, 2000;Tsujimoto and Shimizu, 2000;Gogvadze and Orrenius, 2006). According to the substrate specificities and target Pr, caspases are grouped into ''apoptotic initiator'' such as caspase-9, and ''apoptotic effector'' including caspase-3 (Kaufmann and Hengartner, 2001).…”