Plecita-Hlavata 2015 Am J Respir Cell Mol Biol
|Plecitá-Hlavatá L, Tauber J, Li M, Zhang H, Flockton AR, Pullamsetti SS, Chelladurai P, D'alessandro A, El Kasmi KC, Ježek P, Stenmark KR (2015) Constitutive reprogramming of fibroblast mitochondrial metabolism in pulmonary hypertension. Am J Respir Cell Mol Biol 55:47-57.|
Abstract: Remodeling of the distal pulmonary artery wall is a characteristic feature of pulmonary hypertension (PH). In hypoxic pulmonary hypertension, the most substantial pathologic changes occur in the adventitia. Here, there is marked fibroblast proliferation and profound macrophage accumulation. These fibroblasts (PH-Fibs) maintain a hyperproliferative, apoptotic resistant and pro-inflammatory phenotype in ex vivo culture. Considering that a similar phenotype is observed in cancer cells, where it has been associated at least in part with specific alterations in mitochondrial metabolism, we sought to define the state of mitochondrial metabolism in PH-Fibs. In PH-Fibs pyruvate dehydrogenase was markedly inhibited, resulting in metabolism of pyruvate to lactate, thus consistent with a Warburg-like phenotype. In addition, mitochondrial bioenergetics were suppressed and mitochondrial fragmentation was increased in PH-Fibs. Most importantly, Complex I activity was substantially decreased which was associated with downregulation of the accessory subunit NDUFS4. Due to less efficient ATP synthesis mitochondria were hyperpolarized and mitochondrial superoxide production was increased. This pro-oxidative status was further augmented by simultaneous induction of cytosolic NADPH oxidase 4. While acute and chronic exposure to hypoxia of adventitial fibroblasts from healthy control vessels induced increased glycolysis, it did not induce Complex I deficiency as observed in PH-Fibs. This suggests that hypoxia alone is insufficient to induce NDUFS4 downregulation and constitutive abnormalities in Complex I. In conclusion, our study provides evidence that in the pathogenesis of vascular remodeling in PH, alterations in fibroblast mitochondrial metabolism drive distinct changes in cellular behavior, which potentially occur independently of hypoxia.
• Keywords: Complex I, Adventitial fibroblasts, Mitochondria, Oxidative metabolism, Pulmonary hypertension
• O2k-Network Lab: CZ Prague Jezek P
Labels: MiParea: Respiration, mt-Biogenesis;mt-density, Comparative MiP;environmental MiP Pathology: Other Stress:Oxidative stress;RONS Organism: Human, Bovines Tissue;cell: Endothelial;epithelial;mesothelial cell, Fibroblast Preparation: Intact cells, Isolated mitochondria
Coupling state: LEAK, ROUTINE, OXPHOS, ET Pathway: N, CIV, Other combinations HRR: Oxygraph-2k