Targeting and Regulation of Reactive Oxygen Species Generation by Nox Family NADPH Oxidases

Abstract

Nox family NADPH oxidases serve a variety of functions requiring reactive oxygen species (ROS) generation, including antimicrobial defense, biosynthetic processes, oxygen sensing and redox-based cellular signaling. We explored targeting, assembly, and activation of several Nox family oxidases, since ROS production appears to be regulated both spatially and temporally. Nox1 and Nox3 are similar to the phagocytic (Nox2-based) oxidase, functioning as superoxide-generating multi-component enzymes. Factors regulating their activities include cytosolic activator and organizer proteins and GTP-Rac. Their regulation varies, with the following rank order: Nox2>Nox1>Nox3. Determinants of subcellular targeting include: 1) formation of Nox-p22phox heterodimeric complexes allowing plasma membrane translocation, 2) phospholipids-binding specificities of PX domain-containing organizer proteins (p47phox or Nox organizer 1 (Noxo1)), and 3) variably splicing of Noxo1 PX domains directing them to nuclear or plasma membranes. Dual oxidases (Duox1 and Duox2) are targeted by different mechanisms. Plasma membrane targeting results in H2O2 release, not superoxide, to support extracellular peroxidases. Human Duox1 and Duox2 have no demonstrable peroxidase activity, despite their extensive homology with heme peroxidases. The dual oxidases were reconstituted by Duox activator 2 (Duoxa2) or two Duoxa1 variants, which dictate maturation, subcellular localization, and the type of ROS generated by forming stable complexes with Duox.

Midazolam Induces Cellular Apoptosis in Human Cancer Cells and Inhibits Tumor Growth in Xenograft Mice

“…To elucidate the mechanism responsible for apoptosis induction by midazolam, we investigated the effect of midazolam on intracellular ROS production. ROS generation in cancer cells is observed also through non-mitochondrial sources such as membrane bound NADPH oxidases (Bae et al, 2011;Leto et al, 2009). Nox2 and Nox4 are the membrane bound nonmitochondrial sources of intracellular ROS generation that has been also been associated with the growth promotion in cancer cells (Jeon et al, 2010;Leto et al, 2009;Rao Malla et al, 2010).…”

“…Thus oxidative stress has emerged as an important pathogenic factor in the development of cancer. Mitochondria are the main source of ROS generation; however, non-mitochondrial production of superoxide anion via the NADPH oxidase pathway has also been reported in cancer cells (Leto et al, 2009). ROS generation in cancer cells is observed also through non-mitochondrial sources involving membrane bound NADPH oxidases (Bae et al, 2011;Leto et al, 2009).…”

“…Mitochondria are the main source of ROS generation; however, non-mitochondrial production of superoxide anion via the NADPH oxidase pathway has also been reported in cancer cells (Leto et al, 2009). ROS generation in cancer cells is observed also through non-mitochondrial sources involving membrane bound NADPH oxidases (Bae et al, 2011;Leto et al, 2009). Nox2 and Nox4, located in lipid raft regions of cell membrane, have been associated with the ROS generation and growth promotion in cancer cells (Jeon et al, 2010;Leto et al, 2009;Rao Malla et al, 2010).…”

“…ROS generation in cancer cells is observed also through non-mitochondrial sources involving membrane bound NADPH oxidases (Bae et al, 2011;Leto et al, 2009). Nox2 and Nox4, located in lipid raft regions of cell membrane, have been associated with the ROS generation and growth promotion in cancer cells (Jeon et al, 2010;Leto et al, 2009;Rao Malla et al, 2010). Intrinsic oxidative stress in cancer cells maintains the cell survival (Burdon, 1995;Toyokuni et al, 1995) by activating a variety of redoxsensitive transcription factors such as NF-κB, Nrf2, HIF, and p53 (Trachootham et al, 2008).…”

Effect of inhibitors of NADPH oxidase complex and mitochondrial ATP‐sensitive potassium channels on generation of dopaminergic neurons from neurospheres of mesencephalic precursors

“…However, the source of ROS and the mechanisms involved in the effects have not yet been elucidated. It is known that the NADPH oxidase complex is the most important intracellular source of ROS apart from mitochondria (Babior, 1999(Babior, , 2004Seshiah et al, 2002;Cai et al, 2003) and that it generates and releases ROS in short oxidative bursts for signaling functions (Bokoch and Knaus, 2003;Ritsick et al, 2004;Leto et al, 2009). In addition, several studies support a critical role for mitochondrial ATP-sensitive potassium channels (mitoKATP) in modulating intracellular ROS (Mattson and Liu, 2003;Costa and Garlid, 2008) by means of regulation of the formation/ release of ROS from the mitochondria, and integration of signals from diverse sources Facundo et al, 2007;Fornazari et al, 2008).…”