Cited by 187Redox biology and oxidative stressCell death mechanisms and regulationMitochondrial Function and Pathology

Link between Mitochondria and NADPH Oxidase 1 Isozyme for the Sustained Production of Reactive Oxygen Species and Cell Death

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Lee, Seung Bum, Bae, In Hwa, Bae, Yun Soo, Um, Hong-Duck·2006·Journal of Biological Chemistry

Abstract

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.

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Crossref · 10.1074/jbc.m606702200

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Authors
Lee, S. B., Bae, I. H., Bae, Y. S., & Um, H.-D.
Affiliations
  • Korea Institute of Radiological and Medical Sciences (KR)
  • Ewha Womans University (KR)
Corresponding author
Um, Hong-Duck
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2006-11
Volume
281
Issue
47
Pages
36228-36235
ISSN
0021-9258 (ISSN-L)
OpenAlex
W1979127230
Cited by
187
References
46
Citations by year
2026: 1 · 2025: 4 · 2024: 5 · 2023: 4 · 2022: 2 · 2021: 7 · 2020: 6 · 2019: 10 · 2018: 6 · 2017: 6 · 2016: 5 · 2015: 8 · 2014: 18 · 2013: 15 · 2012: 12
FWCI
4.91
Type
journal article
Language
en
Open access
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Keywords
mitochondria, NOX1, reactive oxygen species, cell death, serum deprivation, phosphatidylinositol 3-kinase, Rac1, Lyn kinase, mitochondrial reactive oxygen species, HEK293T cells, rotenone, potassium cyanide, dominant-negative mutant, siRNA
MeSH terms
NADPH Oxidase 1, Cell Survival, Humans, Mitochondria, NADH, NADPH Oxidoreductases, Signal Transduction, Cell Death, Reactive Oxygen Species, Microscopy, Confocal, src-Family Kinases, NADPH Oxidases, Phosphatidylinositol 3-Kinases, Protein Isoforms, rac1 GTP-Binding Protein, Protein Transport, RNA, Small Interfering

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