TY - JOUR
T1 - Link between mitochondria and NADPH oxidase 1 isozyme for the sustained production of reactive oxygen species and cell death
AU - Seung, Bum Lee
AU - In, Hwa Bae
AU - Yun, Soo Bae
AU - Um, Hong Duck
PY - 2006/11/24
Y1 - 2006/11/24
N2 - Although mitochondria and the Nox family of NADPH oxidase are major sources of reactive oxygen species (ROS) induced by external stimuli, there is limited information on their functional relationship. This study has shown that serum withdrawal promotes the production of ROS in human 293T cells by stimulating both the mitochondria and Nox1. An analysis of their relationship revealed that the mitochondria respond to serum withdrawal within a few minutes, and the ROS produced by the mitochondria trigger Nox1 action by stimulating phosphoinositide 3-kinase (PI3K) and Rac1. Activation of the PI3K/Rac1/Nox1 pathway was evident 4-8 h after but not earlier than serum withdrawal initiation, and this time lag was found to be required for an additional activator of the pathway, Lyn, to be expressed. Functional analysis suggested that, although the mitochondria contribute to the early (0-4 h) accumulation of ROS, the maintenance of the induced ROS levels to the later (4-8 h) phase required the action of the PI3K/Rac1/Nox1 pathway. Serum withdrawal-treated cells eventually lost their viability, which was reversed by blocking either the mitochondria-dependent induction of ROS using rotenone or KCN or the PI3K/Rac1/Nox1 pathway using the dominant negative mutants or small interfering RNAs. This suggests that mitochondrial ROS are essential but not enough to promote cell death, which requires the sustained accumulation of ROS by the subsequent action of Nox1. Overall, this study shows a signaling link between the mitochondria and Nox1, which is crucial for the sustained accumulation of ROS and cell death in serum withdrawal-induced signaling.
AB - Although mitochondria and the Nox family of NADPH oxidase are major sources of reactive oxygen species (ROS) induced by external stimuli, there is limited information on their functional relationship. This study has shown that serum withdrawal promotes the production of ROS in human 293T cells by stimulating both the mitochondria and Nox1. An analysis of their relationship revealed that the mitochondria respond to serum withdrawal within a few minutes, and the ROS produced by the mitochondria trigger Nox1 action by stimulating phosphoinositide 3-kinase (PI3K) and Rac1. Activation of the PI3K/Rac1/Nox1 pathway was evident 4-8 h after but not earlier than serum withdrawal initiation, and this time lag was found to be required for an additional activator of the pathway, Lyn, to be expressed. Functional analysis suggested that, although the mitochondria contribute to the early (0-4 h) accumulation of ROS, the maintenance of the induced ROS levels to the later (4-8 h) phase required the action of the PI3K/Rac1/Nox1 pathway. Serum withdrawal-treated cells eventually lost their viability, which was reversed by blocking either the mitochondria-dependent induction of ROS using rotenone or KCN or the PI3K/Rac1/Nox1 pathway using the dominant negative mutants or small interfering RNAs. This suggests that mitochondrial ROS are essential but not enough to promote cell death, which requires the sustained accumulation of ROS by the subsequent action of Nox1. Overall, this study shows a signaling link between the mitochondria and Nox1, which is crucial for the sustained accumulation of ROS and cell death in serum withdrawal-induced signaling.
UR - http://www.scopus.com/inward/record.url?scp=33845996199&partnerID=8YFLogxK
U2 - 10.1074/jbc.M606702200
DO - 10.1074/jbc.M606702200
M3 - Article
C2 - 17015444
AN - SCOPUS:33845996199
SN - 0021-9258
VL - 281
SP - 36228
EP - 36235
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 47
ER -