Role of Dynamin-Related Protein 1 (Drp1)-Mediated Mitochondrial Fission in Oxygen Sensing and Constriction of the Ductus Arteriosus
- 1 March 2013
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Circulation Research
- Vol. 112 (5), 802-815
- https://doi.org/10.1161/circresaha.111.300285
Abstract
Rationale: Closure of the ductus arteriosus (DA) is essential for the transition from fetal to neonatal patterns of circulation. Initial PO2-dependent vasoconstriction causes functional DA closure within minutes. Within days a fibrogenic, proliferative mechanism causes anatomic closure. Though modulated by endothelial-derived vasodilators and constrictors, O2 sensing is intrinsic to ductal smooth muscle cells and oxygen-induced DA constriction persists in the absence of endothelium, endothelin, and cyclooxygenase mediators. O2 increases mitochondrial-derived H2O2, which constricts ductal smooth muscle cells by raising intracellular calcium and activating rho kinase. However, the mechanism by which oxygen changes mitochondrial function is unknown. Objective: The purpose of this study was to determine whether mitochondrial fission is crucial for O2-induced DA constriction and closure. Methods and Results: Using DA harvested from 30 term infants during correction of congenital heart disease, as well as DA from term rabbits, we demonstrate that mitochondrial fission is crucial for O2-induced constriction and closure. O2 rapidly (2O2 production. Subsequently, fission increases complex I activity. Mitochondrial-targeted catalase overexpression eliminates PO2-induced increases in mitochondrial-derived H2O2 and cytosolic calcium. The small molecule Drp1 inhibitor, Mdivi-1, and siDRP1 yield concordant results, inhibiting O2-induced constriction (without altering the response to phenylephrine or KCl) and preventing O2-induced increases in oxidative metabolism, cytosolic calcium, and ductal smooth muscle cells proliferation. Prolonged Drp1 inhibition reduces DA closure in a tissue culture model. Conclusions: Mitochondrial fission is an obligatory, early step in mammalian O2 sensing and offers a promising target for modulating DA patency.Keywords
This publication has 55 references indexed in Scilit:
- Patent Ductus Arteriosus: Are Current Neonatal Treatment Options Better or Worse Than No Treatment at All?Seminars in Perinatology, 2012
- Inhibition of mitochondrial fission prevents cell cycle progression in lung cancerThe FASEB Journal, 2012
- Pink1 regulates the oxidative phosphorylation machinery via mitochondrial fissionProceedings of the National Academy of Sciences of the United States of America, 2011
- Aberrant mitochondrial fission in neurons induced by protein kinase Cδ under oxidative stress conditions in vivoMolecular Biology of the Cell, 2011
- Small Molecule Inhibitors of Mitochondrial Division: Tools that Translate Basic Biological Research into MedicineCell Chemical Biology, 2010
- Safety and Effectiveness of Indomethacin versus Ibuprofen for Treatment of Patent Ductus ArteriosusAmerican Journal of Perinatology, 2009
- CaM kinase Iα–induced phosphorylation of Drp1 regulates mitochondrial morphologyThe Journal of cell biology, 2008
- Indomethacin promotes nitric oxide function in the ductus arteriosus in the mouseBritish Journal of Pharmacology, 2008
- Chemical Inhibition of the Mitochondrial Division Dynamin Reveals Its Role in Bax/Bak-Dependent Mitochondrial Outer Membrane PermeabilizationDevelopmental Cell, 2008
- Aberrant Chromatin Remodeling by Retinoic Acid Receptor α Fusion Proteins Assessed at the Single-Cell LevelMolecular Biology of the Cell, 2007