04 February 2019

BOLA3 deficiency regulates mitochondrial and glycine metabolism in pulmonary hypertension

Background.

Iron-sulfur (Fe-S) cluster deficiencies have been linked to pulmonary hypertension (PH). An important regulator of Fe-S cluster biogenesis, BolA Family Member 3 (BOLA3) regulates oxidative mitochondrial processes and synthesis of lipoic acid, a key post-translational moiety controlling glycine biosynthesis. Mutations in BOLA3 result in multiple mitochondrial dysfunction syndrome, a fatal disorder associated with PH. However, mechanisms by which BOLA3 drives this disease are not defined.

Results.

In hypoxic pulmonary arterial endothelial cells (PAECs) as well as lungs from human Group 1 and Group 3 PH patients and multiple rodent models of PH, BOLA3 expression was downregulated via a HIF-2α-HDAC-mediated epigenetic axis. In vitro studies in PAECs showed that BOLA3 deficiency decreased Fe-S integrity, impairing mitochondrial complexes and lipoate-contained 2-oxoacid dehydrogenases with consequential increase in glycolysis and alteration in mitochondrial respiration. Via either RNA knockdown or naturally occurring human genetic mutation, BOLA3-deficient cells also showed down-regulated expression of lipoate-dependent glycine cleavage system H protein (GCSH), with elevated accumulation of intracellular glycine. Downstream of altered oxidative metabolism and glycine levels, BOLA3 deficiency increased endothelial proliferation and vasoconstriction, while reducing apoptosis and angiogenesis. RNA-mediated knockdown of endothelial BOLA3 and virus-mediated overexpression of BOLA3 in mouse vasculature in vivo demonstrated that BOLA3 deficiency promotes PH with increased pulmonary vascular remodeling and worsened hemodynamics. Importantly, chronic in vivo supplementation of glycine reversed the protective effects of forced expression of BOLA3 in PH, thus proving that glycine upregulation is essential for the control of PH by BOLA3 deficiency.

Conclusion.

BOLA3 deficiency plays a critical role in promoting endothelial dysfunction and PH via impairment of mitochondrial oxidative respiration and glycine metabolism. These results provide molecular insights for clinical associations of PH with hyperglycinemic syndromes and mitochondrial disorders and identify novel metabolic targets involved in epigenetics, Fe-S cluster biogenesis and glycine homeostasis for diagnostic and therapeutic development

 

Key Contributors

Qiujun Yu1, Yi-Yin Tai1, Ying Tang1, Jingsi Zhao1, Thomas Bertero2, Vinny Negi1, Wei Sun1, Miranda K. Culley1, Jyotsna Pilli1, Karin Brugger3, Johannes A. Mayr3, Rajeev Saggar4, Rajan Saggar5, W. Dean Wallace5, David J. Ross5, Aaron B. Waxman6, Stacy G. Wendell7,8, Steven J. Mullett8, Omar F. Khan9, James E. Dahlman10, Masataka Sugahara1, Nobuyuki Kagiyama1, Taijyu Satoh1, Manling Zhang1, Ning Feng1, John Gorcsan III11, Sara O. Vargas12, Kathleen J. Haley6, Rahul Kumar13, Brian B. Graham13, Robert Langer9,14, Daniel G. Anderson14, Bing Wang15, Sruti Shiva1, and Stephen Y. Chan1 1Center for Pulmonary Vascular Biology and Medicine, Vascular Medicine Institute, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA USA 2Institute for Research on Cancer and Aging, Nice, University of Nice Sophia Antipolis Medical Schools, Nice, France 3Department of Pediatrics, Paracelsus Medical University Salzburg, Salzburg, Austria 4Department of Medicine, University of Arizona, Phoenix, AZ 5Departments of Medicine and Pathology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 6Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 7Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 8Health Sciences Metabolomics and Lipidomics Core, University of Pittsburgh, Pittsburgh, PA 9Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 10Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 11Division of Cardiology, Department of Medicine, Washington University in St. Louis, St. Louis, MO 12Department of Pathology, Boston Children’s Hospital, Boston, MA 13Program in Translational Lung Research, University of Colorado, Denver, Aurora, CO 14David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 15Molecular Therapy Lab, Stem Cell Research Center, University of Pittsburgh School of Medicine, Pittsburgh, PA


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