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

被引:93
作者
Bernard, Karen [1 ]
Logsdon, Naomi J. [1 ]
Miguel, Veronica [5 ]
Benavides, Gloria A. [2 ,3 ]
Zhang, Jianhua [2 ,3 ]
Carter, A. Brent [1 ,4 ]
Darley-Usmar, Victor M. [2 ,3 ]
Thannickal, Victor J. [1 ]
机构
[1] Univ Alabama Birmingham, Div Pulm Allergy & Crit Care Med, Birmingham, AL USA
[2] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA
[3] Univ Alabama Birmingham, Ctr Free Rad Biol & Med, Birmingham, AL USA
[4] Birmingham Vet Adm Med Ctr, Birmingham, AL 35294 USA
[5] UAM, CSIC, Ctr Biol Mol Severo Ochoa, Madrid 28049, Spain
基金
美国国家卫生研究院;
关键词
TRANSCRIPTION-FACTOR-A; ANTIOXIDANT RESPONSE; CONTRACTILE ACTIVITY; SKELETAL-MUSCLE; THYROID-HORMONE; SMOOTH-MUSCLE; COMPLEX I; NRF2; EXPRESSION; ACTIVATION;
D O I
10.1074/jbc.M116.752261
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 gamma coactivator 1-alpha (PGC-1 alpha). 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.
引用
收藏
页码:3029 / 3038
页数:10
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