The Regulation of Reactive Oxygen Species Production during Programmed Cell Death

Abstract

Reactive oxygen species (ROS) are thought to be involved in many forms of programmed cell death. The role of ROS in cell death caused by oxidative glutamate toxicity was studied in an immortalized mouse hippocampal cell line (HT22). The causal relationship between ROS production and glutathione (GSH) levels, gene expression, caspase activity, and cytosolic Ca2+ concentration was examined. An initial 5–10-fold increase in ROS after glutamate addition is temporally correlated with GSH depletion. This early increase is followed by an explosive burst of ROS production to 200–400-fold above control values. The source of this burst is the mitochondrial electron transport chain, while only 5–10% of the maximum ROS production is caused by GSH depletion. Macromolecular synthesis inhibitors as well as Ac-YVAD-cmk, an interleukin 1β–converting enzyme protease inhibitor, block the late burst of ROS production and protect HT22 cells from glutamate toxicity when added early in the death program. Inhibition of intracellular Ca2+ cycling and the influx of extracellular Ca2+ also blocks maximum ROS production and protects the cells. The conclusion is that GSH depletion is not sufficient to cause the maximal mitochondrial ROS production, and that there is an early requirement for protease activation, changes in gene expression, and a late requirement for Ca2+ mobilization.

Coupling mitochondrial respiratory chain to cell death: an essential role of mitochondrial complex I in the interferon-β and retinoic acid-induced cancer cell death

“…It has been documented that electron transport through the MRC is accompanied by the generation of various kinds of free radicals. 23,24 Overproduction of reactive oxygen species (ROS), the by-product of the MRC, causes cell death. 25 We examined whether overproduction of ROS by upregulation of MRC results in apoptosis upon treatment with IFN-b/RA.…”

Protective effect of Bu-7, a flavonoid extracted from Clausena lansium, against rotenone injury in PC12 cells

“…Mitochondria are involved in cell survival and play a central role in apoptotic cell death signaling through the control of cellular energy metabolism, the generation of reactive oxygen species (ROS), and the release of apoptotic factors into the cytosol. Evidence showed that ROS are involved in the apoptotic mechanism of rotenone-mediated neurotoxicity [23] . The mitochondrial membrane permeability transition induces the formation of ROS by the inhibition of the respiratory chain and vice versa [24] .…”

Impaired homeostasis and phenotypic abnormalities in Prdx6−/−mice lens epithelial cells by reactive oxygen species: increased expression and activation of TGFβ

“…In contrast, Prdx6 þ / þ LECs were resistant to identical oxidative stress, demonstrating an antioxidant role of PRDX6. Various reports show that higher levels of ROS are a common signal in different cell death pathways, and indicate a complex relationship between ROS levels and cell death, [48][49][50] in view of the finding that PRDX6-depleted cells bear higher levels of ROS, and are thereby more susceptible to oxidative stress.…”