Mitochondrial-localized NADPH oxidase 4 is a source of superoxide in angiotensin II-stimulated neurons
Open accessAbstract
Angiotensin II (ANG II) plays an important role in the central regulation of systemic cardiovascular function. ANG II-mediated intraneuronal signaling has been shown to be predicated by an increase in mitochondrial superoxide (O 2˙−), yet the source of this reactive oxygen species (ROS) production remains unclear. NADPH oxidase 4 (Nox4), a member of the NADPH oxidase family, has been reported to be localized in mitochondria of various cell types and has been implicated in brain angiotensinergic signaling. However, the subcellular localization and function of Nox4 in neurons has not been fully elucidated. In this study, we hypothesized that Nox4 is expressed in neuron mitochondria and is involved in ANG II-dependent O 2˙−-mediated intraneuronal signaling. To query this, Nox4 immunofluorescent staining and mitochondrial enrichment were performed in a mouse catecholaminergic neuronal cell model (CATH.a). Nox4 was shown to be present in neuron mitochondria as evidenced by colocalization with both the mitochondrial-localized protein manganese superoxide dismutase (MnSOD) and dye MitoTracker Red. Moreover, Nox4 expression was significantly increased in enriched mitochondrial fractions compared with whole cell lysates. Additionally, adenoviral-encoded small interfering RNA for Nox4 (AdsiNox4) caused a robust knockdown in Nox4 mRNA and protein levels, which led to the attenuation of ANG II-induced mitochondrial O 2˙− production. Finally, in the subfornical organ (SFO) of the brain, Nox4 not only demonstrated mitochondrial localization but was induced by chronic, peripheral infusion of ANG II. Collectively, these data suggest that Nox4 is a source of O 2˙− in neuron mitochondria that contributes to ANG II intraneuronal signaling.
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NOX4 has been reported to be localized within the mitochondrion either constitutively or in specific pathological conditions, although controversial.
“Additionally, although controversial, NOX4 has been reported to be localized within the mitochondrion either constitutively or in specific pathological conditions (152, 306, 540).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [152]
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Renal Humoral, Genetic and Genomic Mechanisms Underlying Spontaneous Hypertension
Collett, J. A. (2014) · UKnowledge (University of Kentucky)
- Authors
- Case, A. J., Li, S., Basu, U., Tian, J., & Zimmerman, M. C.
- Affiliations
- University of Nebraska Medical Center (US)
- University of Nebraska–Lincoln (US)
- Corresponding author
- Zimmerman, Matthew C.
- Venue
- American Journal of Physiology-Heart and Circulatory Physiology
- Publisher
- American Physiological Society
- Published
- 2013-07-01
- Volume
- 305
- Issue
- 1
- Pages
- H19-H28
- ISSN
- 0363-6135 (ISSN-L)
- 1522-1539
- PMC
- PMC3727106
- OpenAlex
- W2077983561
- Cited by
- 96
- References
- 41
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 3 · 2023: 3 · 2022: 4 · 2021: 11 · 2020: 11 · 2019: 7 · 2018: 9 · 2017: 12 · 2016: 7 · 2015: 12 · 2014: 8 · 2013: 5
- FWCI
- 7.43
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Physiology-Heart and Circulatory Physiology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01HL103942)
- National Center for Research Resources (P20RR017675)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
- Keywords
- NOX4, angiotensin II, mitochondrial superoxide, reactive oxygen species, subfornical organ, catecholaminergic neurons, manganese superoxide dismutase, cardiovascular regulation
- MeSH terms
- NADPH Oxidase 4, Angiotensin II, Animals, Cell Line, Mice, Inbred C57BL, Mitochondria, Neurons, Superoxides, Superoxide Dismutase, Signal Transduction, Gene Expression, NADPH Oxidases, RNA, Small Interfering, Mice
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