期刊
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
卷 310, 期 1, 页码 C80-C88出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpcell.00073.2015
关键词
microtubules; nitric oxide; mitochondria; bioenergetics
资金
- CRI Start-up funds from the Children's Hospital of Wisconsin
- CTSI Pilot Award [UL1TR000055]
- NIH [R03-HD-073274, R03-HD-65841, R01-HL-057268]
- Muma Endowed Chair in Neonatology and Children's Research Institute
Nitration of both protein-bound and free tyrosine by reactive nitrogen species results in the formation of nitrotyrosine (NT). We previously reported that free NT impairs microtubule polymerization and uncouples endothelial nitric oxide synthase (eNOS) function in pulmonary artery endothelial cells (PAEC). Because microtubules modulate mitochondrial function, we hypothesized that increased NT levels during inflammation and oxidative stress will lead to mitochondrial dysfunction in PAEC. PAEC isolated from fetal lambs were exposed to varying concentrations of free NT. At low concentrations (1-10 mu M), NT increased nitration of mitochondrial electron transport chain (ETC) protein subunit complexes I-V and state III oxygen consumption. Higher concentrations of NT (50 mu M) caused decreased microtubule acetylation, impaired eNOS interactions with mitochondria, and decreased ETC protein levels. We also observed increases in heat shock protein-90 nitration, mitochondrial superoxide formation, and fragmentation of mitochondria in PAEC. Our data suggest that free NT accumulation may impair microtubule polymerization and exacerbate reactive oxygen species-induced cell damage by causing mitochondrial dysfunction.
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