Asymmetric Dimethylarginine Induces Endothelial Nitric-oxide Synthase Mitochondrial Redistribution through the Nitration-mediated Activation of Akt1*
Open accessAbstract
Background: Asymmetric dimethylarginine (ADMA) can induce endothelial nitric-oxide synthase (eNOS) redistribution from the plasma membrane to the mitochondria. Results: AMDA induces nitration of Akt1 at Tyr 350 within the client-binding domain, increasing its activation and enhancing eNOS phosphorylation. Conclusion: Under physiologic conditions, Akt1-mediated redistribution of eNOS to the mitochondria enhances mitochondrial coupling. Significance: Reducing Akt1 nitration may reduce the deleterious effects of Akt1 signaling in various pathologies. We have recently demonstrated that asymmetric dimethylarginine (ADMA) induces the translocation of endothelial nitric-oxide synthase (eNOS) to the mitochondrion via a mechanism that requires protein nitration. Thus, the goal of this study was elucidate how eNOS redistributes to mitochondria and to identify the nitrated protein responsible for this event. Our data indicate that exposure of pulmonary arterial endothelial cells to ADMA enhanced eNOS phosphorylation at the Akt1-dependent phosphorylation sites Ser 617 and Ser 1179 . Mutation of these serine residues to alanine (S617A and S1179A) inhibited nitration-mediated eNOS translocation to the mitochondria, whereas the phosphormimic mutations (S617D and S1179D) exhibited increased mitochondrial redistribution in the absence of ADMA. The overexpression of a dominant-negative Akt1 also attenuated ADMA-mediated eNOS mitochondrial translocation. Furthermore, ADMA enhanced Akt1 nitration and increased its activity. Mass spectrometry identified a single nitration site in Akt1 located at the tyrosine residue (Tyr 350 ) located within the client-binding domain. Replacement of Tyr 350 with phenylalanine abolished peroxynitrite-mediated eNOS translocation to mitochondria. We also found that in the absence of ADMA, eNOS translocation decreased mitochondrial oxygen consumption and superoxide production without altering cellular ATP level. This suggests that under physiologic conditions, eNOS translocation enhances mitochondria coupling. In conclusion, we have identified a new mechanism by which eNOS translocation to mitochondria is regulated by the phosphorylation of eNOS at Ser 617 and Ser 1179 by Akt1 and that this is enhanced when Akt1 becomes nitrated at Tyr 350 .
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Peroxynitrite can abstract a hydrogen atom to initiate lipid peroxidation, a detrimental process that can lead to cytotoxicity.
“For example, lipids are also a significant biological target for peroxynitrite, and although the species can abstract a hydrogen atom to initiate lipid peroxidation, a detrimental process that can lead to cytotoxicity in many cases (65, 766), peroxynitrite can also mediate lipid nitration (54, 1027).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [766]
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Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation
Tejero, J., Shiva, S., & Gladwin, M. T. (2019) · Physiological Reviews · doi:10.1152/physrev.00036.2017 · Cited by 541 · see citing works
- Authors
- Rafikov, R., Rafikova, O., Aggarwal, S., Gross, C., Sun, X., Desai, J., Fulton, D., & Black, S. M.
- Corresponding author
- Black, Stephen M.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2013-03
- Volume
- 288
- Issue
- 9
- Pages
- 6212-6226
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3585057
- OpenAlex
- W1968959115
- Cited by
- 36
- References
- 84
- Citations by year
- 2024: 2 · 2023: 3 · 2021: 1 · 2020: 4 · 2019: 5 · 2018: 2 · 2017: 2 · 2016: 7 · 2015: 5 · 2014: 3 · 2013: 2
- FWCI
- 2.14
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Fondation Leducq
- National Institutes of Health (HL101902)
- National Heart, Lung, and Blood Institute (HL60190, HL-67841, HL101902, R01HL067841, P01HL101902, R01HL060190)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer-related gene regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- asymmetric dimethylarginine, endothelial nitric oxide synthase, AKT1, protein nitration, mitochondrial translocation, eNOS phosphorylation, peroxynitrite, mitochondrial coupling, superoxide production, mitochondrial oxygen consumption, pulmonary artery endothelial cells, nitric oxide bioavailability, nitric oxide synthase inhibition, endothelial dysfunction, hypertension, atherosclerosis
- MeSH terms
- Animals, Arginine, Cells, Cultured, Enzyme Activation, Enzyme Inhibitors, Humans, Mitochondria, Oxygen Consumption, Phosphorylation, Sheep, Protein Transport, Mitochondrial Proteins, Proto-Oncogene Proteins c-akt, Mice, Nitric Oxide Synthase Type III
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