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Antioxid Redox Signal. 2015 Nov 10;23(14):1106-12. doi: 10.1089/ars.2014.6238. Epub 2015 Aug 3.

NOX4 in Mitochondria: Yeast Two-Hybrid-Based Interaction with Complex I Without Relevance for Basal Reactive Oxygen Species?

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1 Physiologisches Institut, Justus-Liebig Universität , Gießen, Germany .
2 Neuroscience Institute , CNR, Padova, Italy .
3 Dipartimento di Scienze Biomediche, Università degli Studi di Padova , Padova, Italy .
4 King's College London , BHF Centre of Excellence, The James Black Centre, London, United Kingdom .
5 Department of Pharmacology, CARIM, and Maastricht Institute for Advanced Studies, Maastricht University , Maastricht, The Netherlands .


NADPH oxidases (NOXs) represent the only known dedicated source of reactive oxygen species (ROS) and thus a prime therapeutic target. Type 4 NOX is unique as it produces H2O2, is constitutively active, and has been suggested to localize to cardiac mitochondria, thus possibly linking mitochondrial and NOX-derived ROS formation. The aim of this study was to identify NOX4-binding proteins and examine the possible physiological localization of NOX4 to mitochondria and its impact on mitochondrial ROS formation. We here provide evidence that NOX4 can, in principle, enter protein-protein interactions with mitochondrial complex I NADH dehydrogenase subunits, 1 and 4L. However, under physiological conditions, NOX4 protein was neither detectable in the kidney nor in cardiomyocyte mitochondria. The NOX inhibitor, GKT136901, slightly reduced ROS formation in cardiomyocyte mitochondria, but this effect was observed in both wild-type and Nox4(-/-) mice. NOX4 may thus associate with mitochondrial complex I proteins, but in cardiac and renal mitochondria under basal conditions, expression is beyond our detection limits and does not contribute to ROS formation.

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