Downregulation of lung mitochondrial prohibitin in COPD

Respir Med. 2012 Jul;106(7):954-61. doi: 10.1016/j.rmed.2012.03.019. Epub 2012 Apr 20.

Abstract

Prohibitins (PHB1 and PHB2) are versatile proteins located at the inner mitochondrial membrane, maintaining normal mitochondrial function and morphology. They interact with the NADH dehydrogenase protein complex, which is essential for oxidoreductase activity within cells. However, their expression in lung epithelium, especially in smokers and patients with inflammatory lung diseases associated with increased oxidative stress, such as COPD, is unknown. Lung tissue specimens from 45 male subjects were studied: 20 COPD patients [age: 65.7 ± 5.8 years, smoking: 84.6 ± 33.6 pack-years, FEV(1) (%pred.): 58.7 ± 14.6, FEV(1)/FVC (%): 63.8 ± 9.4], 15 non-COPD smokers [age: 59.0 ± 12.1 years, smoking: 52.5 ± 20.8 pack-years, FEV(1) (%pred.): 85.5 ± 14.2, FEV(1)/FVC (%): 78.5 ± 4.7] and 10 non-smokers. Quantitative real-time PCR experiments were carried out for PHB1 and PHB2, using β-actin as internal control. Non-COPD smokers exhibited lower PHB1 mRNA levels when compared to non-smokers (0.55 ± 0.06 vs. 0.90 ± 0.06, P = 0.043), while PHB1 expression was even further decreased in COPD patients (0.32 ± 0.02), a statistically significant finding vs. both non-COPD smokers (P = 0.040) and non-smokers (P < 0.001). By contrast, PHB2 levels were similar among the three study groups. Western blot analysis for the PHB1 protein verified the qPCR results (non-smokers: 1.77 ± 0.13; non-COPD smokers: 0.97 ± 0.08; COPD patients: 0.59 ± 0.10, P = 0.007). Further analysis revealed that PHB1 downregulation in COPD patients cannot be attributed solely to smoking, and that PHB1 expression levels are associated with the degree of airway obstruction [FEV(1) (P(mRNA) = 0.004, P(protein) = 0.014)]. The significant downregulation of PHB1 in COPD and non-COPD smokers in comparison to non-smokers possibly reflects a distorted mitochondrial function due to decreased mitochondrial stability, especially in the mitochondria of COPD patients.

MeSH terms

  • Aged
  • Blotting, Western
  • DNA, Complementary / metabolism
  • Down-Regulation
  • Forced Expiratory Volume / physiology
  • Humans
  • Lung / metabolism*
  • Male
  • Middle Aged
  • Mitochondria / metabolism
  • Mitochondrial Membranes / metabolism
  • Oxidative Stress / physiology
  • Pulmonary Disease, Chronic Obstructive / metabolism*
  • Pulmonary Disease, Chronic Obstructive / physiopathology
  • RNA, Messenger / metabolism
  • Reactive Oxygen Species / metabolism
  • Real-Time Polymerase Chain Reaction
  • Repressor Proteins / metabolism*
  • Smoking / metabolism
  • Vital Capacity / physiology

Substances

  • DNA, Complementary
  • RNA, Messenger
  • Reactive Oxygen Species
  • Repressor Proteins
  • prohibitin