162 - Decreased Taurine Transport and Impaired Alveolar Formation in Hyperoxia Neonatal Rat Lungs

Hyperoxia (HOX) causes bronchopulmonary dysplasia (BPD) in rodent pups. Increased endoplasmic reticulum (ER) stress is reported in rat BPD model. ER stress impairs solute transporters, including taurine transporter (SLC6A6), by suppressing glycosylation. Taurine is required for subunits of mitochondrial electron transport chain (ETC) proteins. The role of taurine depletion in impaired ETC activity in HOX neonatal lungs has not been explored.  

Objective:

To investigate if ER stress causes taurine depletion and subsequent ETC impairment in hyperoxia neonatal lungs.

Design/Methods:

Sprague-Dawley rat pups were raised in 21% or >90% oxygen with alternating nursing dams between P1 and P10. Lung and serum were snap-frozen for untargeted metabolomics, transcriptomics (Affymetrix), and immunoblots at P10. Metaboanalyst 5.0 and g:Profiler were used for data analysis. Immunoprecipitation was used to study protein ubiquitination and glycosylation. Daily taurine (100 mg/kg) was given as the rescue study.

Results:

ETC transcripts and protein levels increased in HOX lungs suggesting enhanced oxidative phosphorylation. Paradoxically, the ATP content (1.6±0.3x10⁶ IS vs. 2.1±0.5x10⁶ IS, p=0.07) and complex-1 activity (1.3±0.1x10^-4 vs. 3.5±0.2x10^-4 OD/min/20 µg of protein, p< 0.01) were decreased in the presence of higher glucose content (13.5±2.0x10⁵ IS vs. 7.7±1.4x10⁵ IS, p=0.02). The expression of taurine-modulated complex-1 subunits – ND5 (0.5±0.2 vs. 1.0±0.2, p< 0.01) and ND6 (0.2±0.1 vs. 1.0±0.1, p< 0.01) – decreased in HOX lungs. Taurine decreased in HOX lungs (2.7±1.7x10⁶ IS vs. 6.2±1.1x10⁶ IS, p< 0.01) but increased in corresponding serum (9.1±1.5x10⁴ IS vs. 4.9±0.8x10⁴ IS, p< 0.05) which corroborated the decreased SLC6A6 expression (0.1±0.1 vs. 1.0±0.3, p< 0.01). Decreased glycosylation (0.1±0.1 vs. 1.0±0.3, p< 0.01) and increased ubiquitination (2.7±0.7 vs. 1.0±0.3, p< 0.01) indicated an increased degradation of SLC6A6 in HOX lungs. Taurine improved alveolar formation in HOX lungs.

Conclusion(s):

Decreased taurine level explains the paradoxically increased ETC protein expression with decreased ETC activity in HOX lungs. ER stress-associated degradation reasonably explains the decreased SLC6A6 expression and taurine transport. Taurine treatment can attenuate BPD severity.