Page 1 - G. Cell differentiation. division. and death

Mitochondrial reactive oxygen species in TNFα-induced necroptosis

Ji Young Lee, and Sang Won Kang
Department of Life Science, Ewha Womans University, Seoul 03760, Korea

BACKGROUND AIM

Cell death is essential for homeostasis in organisms on removing damaged, degenerated or infected cells. Balance The role of Reactive Oxygen Species (ROS) is crucial in the regulation of various cellular
between cell death and cell proliferation is important. Resistance to cell death can lead to cancer and other diseases, activity including cell death. ROS is a general term containing chemical species derived
while uncontrolled cell death can lead to a variety of diseases, including necrotic-related and autoimmune diseases. from oxygen. However, it is still unclear as to which specific type of ROS is involved in cell
Later, as research into cell death mechanisms and signal transduction pathways progressed, cell death is classified
into regulated cell death (RCD) and accidental cell death (ACD). ACD is triggered by unexpected damage and injury death pathway, leading to arguments arising about the classification of ROS in
and it is biologically uncontrolled. In contrast, RCD has specific signaling cascades, so RCD can be regulated by necroptosis. Here, we show that tumor necrosis factor-α (TNFα)-induced necroptosis
defined effector molecules executing specific pathway. Reactive oxygen species (ROS) is generated from normal accompanies with mitochondrial superoxide anion. Similar to necroptosis, mitochondria
cellular activity and plays an important role in various cellular activities, including cell differentiation and gene superoxide anion is regulated by a necroptosis kinase, receptor-interacting protein 3
expression. ROS includes the superoxide anion (O2˙ˉ), hydrogen peroxide (H2O2), and hydroxyl radical (OH). ROS (RIP3). Since the level of mitochondrial superoxide anion increases in TNFα-induced
is not only a product of cellular activity but also known as a second messenger that plays an important role in signal
transduction such as specific cytokines and growth factors. Since previous study showed that the 2-Cys necroptosis, we investigated NADPH oxidase (NOX) as one of ROS generating systems
peroxiredoxin (Prx) isoforms, Prx I and Prx II, regulate different apoptosis pathways via H2O2, I wonder which type of in cells. APX-115 (NOX inhibitor) decreases level of mitochondrial superoxide anion
ROS is involved in what process in necroptosis. Reactive oxygen species (ROS) is robustly produced during the cell generated in TNFα-induced necroptosis. More importantly, we showed that the inhibition
death. However, few studies have identified types of ROS in different cell death pathways. In this study, I found of mitochondrial superoxide anion production does not contribute to necroptosis directly.
difference of ROS type dependent on cell death pathway and their mechanism. Unexpectedly, mitochondrial Overall, this study implicates mitochondrial superoxide anion in TNFα-induced necroptosis
superoxide anion is produced by NOX in TNFα-induced necroptosis. Thus, this study demonstrates NOX is source of
mitochondrial superoxide anion TNFα-induced necroptosis and it does not contribute to cell death directly. to be the product of TNFα-induced necroptosis.
RESULTS

CONCLUSION METHODS
Mitochondrial superoxide occurred during TNFα-induced necroptosis in RIP3 Cell death assay NADH/NAD+ assay
expression positive cells, and NOX was involved in the process. Although NOX Measurement of intracellular ROS Immunoblotting
inhibitor reduced level of mitochondrial superoxide anion, TNFα-induced necroptosis REFERENCES
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clarified. Which NOX isoform plays a role in TNFα-induced necroptosis is not yet Subtypes I and II Exacerbates TNF-alpha-Induced Apoptosis via Different
clear. Further studies are required to confirm interaction NOX and necroptosis. This Routes. Cell Rep 26, 2194-2211 e2196
finding will be a valuable discovery of a novel necroptosis regulatory mechanism. Contact information
Here, we present evidence that increased mitochondrial superoxide anion would be
the product rather than the cause of TNFα-induced necroptosis. Ji Young Lee: lwldud96@ewhain.net