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Mitochondrial dynamics in pulmonary arterial hypertension

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Abstract

Pulmonary arterial hypertension (PAH) is an idiopathic cardiopulmonary disease characterized by obstruction of small pulmonary arteries. Vascular obstruction is the consequence of excessive proliferation and apoptosis resistance of vascular cells, as well as inflammation, thrombosis, and vasoconstriction. Vascular obstruction increases the afterload faced by the right ventricle (RV), leading to RV failure. The proliferative, obstructive vasculopathy of PAH shares several mitochondrial abnormalities with cancer, notably a shift to aerobic glycolysis and mitochondrial fragmentation. Mitochondria in the pulmonary artery smooth muscle cell (PASMC) normally serve as oxygen sensors. In PAH, acquired mitochondrial abnormalities, including epigenetic silencing of superoxide dismutase (SOD2), disrupt oxygen sensing creating a pseudo-hypoxic environment characterized by normoxic activation of hypoxia-inducible factor-1α (HIF-1α). The resulting metabolic shift to aerobic glycolysis (the Warburg phenomenon) reflects inhibition of pyruvate dehydrogenase by pyruvate dehydrogenase kinases. In addition, altered mitochondrial dynamics result in mitochondrial fragmentation. The molecular basis of this structural change includes upregulation and activation of fission mediators, notably dynamin-related protein 1 (DRP-1), and downregulation of fusion mediators, especially mitofusin-2 (MFN2). These pathogenic mitochondrial abnormalities offer new therapeutic targets. Inhibition of mitotic fission or enhancement of fusion in PAH PASMC slows cell proliferation, causes cell cycle arrest, and induces apoptosis. DRP-1 inhibition or MFN2 gene therapy can regress PAH in experimental models of PAH. This review focuses on the etiology of mitochondrial fragmentation in PAH and explores the therapeutic implications of mitochondrial dynamics in the pulmonary vasculature and RV.

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Acknowledgments

Supported by NIH-RO1-HL071115, 1RC1HL099462-01 (S.A.) and the American Heart Association (AHA), CIHR Vascular Network (A.D.).

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Patent for use of PDK inhibitors in cancer (not commercialized).

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Authors and Affiliations

  1. Division of Cardiovascular Medicine, Department of Medicine, University of Utah, Salt Lake City, UT, USA

    John Ryan & Jessica Huston

  2. Department of Medicine, Queen’s University, Etherington Hall, Room 3041, 94 Stuart St., Kingston, ON, K7L 3N6, Canada

    Asish Dasgupta, Kuang-Huieh Chen & Stephen L. Archer

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Ryan, J., Dasgupta, A., Huston, J. et al. Mitochondrial dynamics in pulmonary arterial hypertension. J Mol Med 93, 229–242 (2015). https://doi.org/10.1007/s00109-015-1263-5

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  • DOI: https://doi.org/10.1007/s00109-015-1263-5

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