Complex I dysfunction underlies the glycolytic switch in pulmonary hypertensive smooth muscle cells

Ruslan Rafikov, Xutong Sun, Olga Rafikova, Mary Louise Meadows, Ankit A. Desai, Zain Khalpey, Jason X.J. Yuan, Jeffrey R. Fineman, Stephen M. Black

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69 Scopus citations


ATP is essential for cellular function and is usually produced through oxidative phosphorylation. However, mitochondrial dysfunction is now being recognized as an important contributing factor in the development cardiovascular diseases, such as pulmonary hypertension (PH). In PH there is a metabolic change from oxidative phosphorylation to mainly glycolysis for energy production. However, the mechanisms underlying this glycolytic switch are only poorly understood. In particular the role of the respiratory Complexes in the mitochondrial dysfunction associated with PH is unresolved and was the focus of our investigations. We report that smooth muscle cells isolated from the pulmonary vessels of rats with PH (PH-PASMC), induced by a single injection of monocrotaline, have attenuated mitochondrial function and enhanced glycolysis. Further, utilizing a novel live cell assay, we were able to demonstrate that the mitochondrial dysfunction in PH-PASMC correlates with deficiencies in the activities of Complexes I-III. Further, we observed that there was an increase in mitochondrial reactive oxygen species generation and mitochondrial membrane potential in the PASMC isolated from rats with PH. We further found that the defect in Complex I activity was due to a loss of Complex I assembly, although the assembly of Complexes II and III were both maintained. Thus, we conclude that loss of Complex I assembly may be involved in the switch of energy metabolism in smooth muscle cells to glycolysis and that maintaining Complex I activity may be a potential therapeutic target for the treatment of PH.

Original languageEnglish (US)
Pages (from-to)278-286
Number of pages9
JournalRedox Biology
StatePublished - Dec 1 2015


  • Electron transport chain
  • Mitochondria
  • Pulmonary hypertension
  • Warburg effect

ASJC Scopus subject areas

  • Organic Chemistry

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