Mitochondrial metabolism in pulmonary hypertension: beyond mountains there are mountains
Miranda K. Culley, Stephen Y. Chan
Miranda K. Culley, Stephen Y. Chan
Published August 31, 2018; First published August 6, 2018
Citation Information: J Clin Invest. 2018;128(9):3704-3715. https://doi.org/10.1172/JCI120847.
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Category: Review Series

Mitochondrial metabolism in pulmonary hypertension: beyond mountains there are mountains

Abstract

Pulmonary hypertension (PH) is a heterogeneous and fatal disease of the lung vasculature, where metabolic and mitochondrial dysfunction may drive pathogenesis. Similar to the Warburg effect in cancer, a shift from mitochondrial oxidation to glycolysis occurs in diseased pulmonary vessels and the right ventricle. However, appreciation of metabolic events in PH beyond the Warburg effect is only just emerging. This Review discusses molecular, translational, and clinical concepts centered on the mitochondria and highlights promising, controversial, and challenging areas of investigation. If we can move beyond the “mountains” of obstacles in this field and elucidate these fundamental tenets of pulmonary vascular metabolism, such work has the potential to usher in much-needed diagnostic and therapeutic approaches for the mitochondrial and metabolic management of PH.

Authors

Miranda K. Culley, Stephen Y. Chan

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Figure 1

Metabolic pathways disrupted in PH: the Warburg effect.

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Metabolic pathways disrupted in PH: the Warburg effect. The mitochondria...
The mitochondria in pulmonary vascular cells and the right ventricle in PH exhibit decreased oxidative phosphorylation and increased glycolysis, consistent with the Warburg effect. Following a decrease of respiratory activity, transcriptional upregulation and stabilization of HIF-α mediates compensatory glycolytic reprogramming, which includes increased glucose transporter 1 (GLUT1); hexokinase (HK), which traps glucose via conversion to glucose-6-phosphate (G6P); and lactate dehydrogenase (LDHA), which converts pyruvate to lactic acid. At the same time, there is increased activity of pyruvate kinase isoform M2 (PKM2), which slows the production of pyruvate from phosphoenolpyruvate (PEP), and reduced pyruvate dehydrogenase (PDH) activity, driven by elevated pyruvate dehydrogenase kinase (PDK1/2). The Warburg effect promotes cell survival and proliferation, and simultaneous hyperpolarization of the mitochondrial membrane potential promotes evasion of mitochondria-dependent apoptosis. This metabolic switch in pulmonary vascular cells drives extensive remodeling that further results in increased pulmonary vascular resistance and pulmonary artery pressures. ETC, electron transport chain; HRE, hypoxia-response element.