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J Biol Chem. 2017 Feb 17;292(7):3029-3038. doi: 10.1074/jbc.M116.752261. Epub 2017 Jan 3.

NADPH Oxidase 4 (Nox4) Suppresses Mitochondrial Biogenesis and Bioenergetics in Lung Fibroblasts via a Nuclear Factor Erythroid-derived 2-like 2 (Nrf2)-dependent Pathway.

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From the Division of Pulmonary, Allergy, and Critical Care Medicine,
From the Division of Pulmonary, Allergy, and Critical Care Medicine.
Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid (UAM), 28049 Madrid, Spain.
Department of Pathology, and.
Center for Free Radicals Biology and Medicine, University of Alabama at Birmingham and.
Birmingham Veterans Administration Medical Center, Birmingham, Alabama 35294 and.


Mitochondrial bioenergetics are critical for cellular homeostasis and stress responses. The reactive oxygen species-generating enzyme, NADPH oxidase 4 (Nox4), regulates a number of physiological and pathological processes, including cellular differentiation, host defense, and tissue fibrosis. In this study we explored the role of constitutive Nox4 activity in regulating mitochondrial function. An increase in mitochondrial oxygen consumption and reserve capacity was observed in murine and human lung fibroblasts with genetic deficiency (or silencing) of Nox4. Inhibition of Nox4 expression/activity by genetic or pharmacological approaches resulted in stimulation of mitochondrial biogenesis, as evidenced by elevated mitochondrial-to-nuclear DNA ratio and increased expression of the mitochondrial markers transcription factor A (TFAM), citrate synthase, voltage-dependent anion channel (VDAC), and cytochrome c oxidase subunit 4 (COX IV). Induction of mitochondrial biogenesis was dependent on TFAM up-regulation but was independent of the activation of the peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α). The enhancement of mitochondrial bioenergetics as well as the increase in mitochondrial proteins in Nox4-deficient lung fibroblasts is inhibited by silencing of nuclear factor erythroid-derived 2-like 2 (Nrf2), supporting a key role for Nrf2 in control of mitochondrial biogenesis. Together, these results indicate a critical role for both Nox4 and Nrf2 in counter-regulation of mitochondrial biogenesis and metabolism.


NADPH oxidase; NADPH oxidase-4; Nuclear factor 2 (erythroid-derived 2-like factor) (NFE2L2) (Nrf2); bioenergetics; fibroblast; mitochondria; mitochondrial biogenesis; mitochondrial transcription factor A

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