NOX5: molecular biology and pathophysiology

Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (Nox), comprise seven family members (Nox1–Nox5 and dual oxidase 1 and 2) and are major producers of reactive oxygen species in mammalian cells. Reactive oxygen species are crucially involved in cell signalling and function. All Noxs share structural homology comprising six transmembrane domains with two haem‐binding regions and an NADPH‐binding region on the intracellular C‐terminus, whereas their regulatory systems, mechanisms of activation and tissue distribution differ. This explains the diverse function of Noxs. Of the Noxs, NOX5 is unique in that rodents lack the gene, it is regulated by Ca2+, it does not require NADPH oxidase subunits for its activation, and it is not glycosylated. NOX5 localizes in the perinuclear and endoplasmic reticulum regions of cells and traffics to the cell membrane upon activation. It is tightly regulated through numerous post‐translational modifications and is activated by vasoactive agents, growth factors and pro‐inflammatory cytokines. The exact pathophysiological significance of NOX5 remains unclear, but it seems to be important in the physiological regulation of sperm motility, vascular contraction and lymphocyte differentiation, and NOX5 hyperactivation has been implicated in cardiovascular disease, kidney injury and cancer. The field of NOX5 biology is still in its infancy, but with new insights into its biochemistry and cellular regulation, discovery of the NOX5 crystal structure and genome‐wide association studies implicating NOX5 in disease, the time is now ripe to advance NOX5 research. This review provides a comprehensive overview of our current understanding of NOX5, from basic biology to human disease, and highlights the unique characteristics of this enigmatic Nox isoform

SS18 Together with Animal-Specific Factors Defines Human BAF-Type SWI/SNF Complexes

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Acute in vitro hypoxia and high-altitude (4,559 m) exposure decreases leukocyte oxygen consumption.

Hypoxia impairs metabolic functions by decreasing activity and expression of ATP-consuming processes. To separate hypoxia from systemic effects, we tested whether hypoxia at high altitude affects basal and PMA-stimulated leukocyte metabolism and how this compares to acute (15 min) and 24 h of in vitro hypoxia. Leukocytes were prepared at low altitude and ∼24 h after arrival at 4559 m. Mitochondrial oxygen consumption (JO₂) was measured by respirometry, oxygen radicals by electron spin resonance spectroscopy, both at a Po₂ = 100 mmHg (JO₂,₁₀₀) and 20 mmHg (JO₂,₂₀). Acute hypoxia of leukocytes decreased JO₂ at low altitude. Exposure to high altitude decreased JO₂,₁₀₀, whereas JO₂,₂₀ was not affected. Acute hypoxia of low-altitude samples decreased the activity of complexes I, II, and III. At high altitude, activity of complexes I and III were decreased when measured in normoxia. Stimulation of leukocytes with PMA increased JO₂,₁₀₀ at low (twofold) and high altitude (five-fold). At both locations, PMA-stimulated JO₂ was decreased by acute hypoxia. Basal and PMA-stimulated reactive oxygen species (ROS) production were unchanged at high altitude. Separate in vitro experiments performed at low altitude show that ∼75% of PMA-induced increase in JO₂ was due to increased extra-mitochondrial JO₂ (JO₂(,res); in the presence of rotenone and antimycin A). JO₂(,res) was doubled by PMA. Acute hypoxia decreased basal JO₂(,res) by ∼70% and PMA-stimulated JO₂(,res) by about 50% in cells cultured in normoxia and hypoxia (1.5% O₂; 24 h). Conversely, 24 h in vitro hypoxia decreased mitochondrial JO₂,₁₀₀ and JO₂,₂₀, extra-mitochondrial, basal, and PMA-stimulated JO₂ were not affected. These results show that 24 h of high altitude but not 24 h in vitro hypoxia decreased basal leukocyte metabolism, whereas PMA-induced JO₂ and ROS formation were not affected, indicating that prolonged high-altitude hypoxia impairs mitochondrial metabolism but does not impair respiratory burst. In contrast, acute hypoxia impairs respiratory burst at either altitude.Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe