Role of Dynamin-Related Protein 1 (Drp1)-Mediated Mitochondrial Fission in Oxygen Sensing and Constriction of the Ductus Arteriosus

Zhigang Hong, Shelby Kutty, Peter T. Toth, Glenn Marsboom, James M Hammel, Carolyn Chamberlain, John J. Ryan, Hannah J. Zhang, Willard W. Sharp, Erik Morrow, Kalyani Trivedi, E. Kenneth Weir, Stephen L. Archer

Research output: Contribution to journalArticle

58 Citations (Scopus)

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 (<5 minutes) causes mitochondrial fission by a cyclin-dependent kinase- mediated phosphorylation of dynamin-related protein 1 (Drp1) at serine 616. Fission triggers a metabolic shift in the ductal smooth muscle cells that activates pyruvate dehydrogenase and increases mitochondrial H2O2 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.

Original languageEnglish (US)
Pages (from-to)802-815
Number of pages14
JournalCirculation Research
Volume112
Issue number5
DOIs
StatePublished - Mar 1 2013

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Mitochondrial Dynamics
Dynamins
Ductus Arteriosus
Constriction
Oxygen
Smooth Muscle Myocytes
Proteins
Calcium
rho-Associated Kinases
Patent Ductus Arteriosus
Cyclin-Dependent Kinases
Endothelins
Phenylephrine
Prostaglandin-Endoperoxide Synthases
Vasoconstriction
Pyruvic Acid
Vasodilator Agents
Catalase
Serine
Endothelium

Keywords

  • Mdivi-1 compound
  • green fluorescent protein
  • mitochondrial dynamics
  • oxygen sensing
  • patent ductus arteriosus

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Role of Dynamin-Related Protein 1 (Drp1)-Mediated Mitochondrial Fission in Oxygen Sensing and Constriction of the Ductus Arteriosus. / Hong, Zhigang; Kutty, Shelby; Toth, Peter T.; Marsboom, Glenn; Hammel, James M; Chamberlain, Carolyn; Ryan, John J.; Zhang, Hannah J.; Sharp, Willard W.; Morrow, Erik; Trivedi, Kalyani; Weir, E. Kenneth; Archer, Stephen L.

In: Circulation Research, Vol. 112, No. 5, 01.03.2013, p. 802-815.

Research output: Contribution to journalArticle

Hong, Z, Kutty, S, Toth, PT, Marsboom, G, Hammel, JM, Chamberlain, C, Ryan, JJ, Zhang, HJ, Sharp, WW, Morrow, E, Trivedi, K, Weir, EK & Archer, SL 2013, 'Role of Dynamin-Related Protein 1 (Drp1)-Mediated Mitochondrial Fission in Oxygen Sensing and Constriction of the Ductus Arteriosus', Circulation Research, vol. 112, no. 5, pp. 802-815. https://doi.org/10.1161/CIRCRESAHA.111.300285
Hong, Zhigang ; Kutty, Shelby ; Toth, Peter T. ; Marsboom, Glenn ; Hammel, James M ; Chamberlain, Carolyn ; Ryan, John J. ; Zhang, Hannah J. ; Sharp, Willard W. ; Morrow, Erik ; Trivedi, Kalyani ; Weir, E. Kenneth ; Archer, Stephen L. / Role of Dynamin-Related Protein 1 (Drp1)-Mediated Mitochondrial Fission in Oxygen Sensing and Constriction of the Ductus Arteriosus. In: Circulation Research. 2013 ; Vol. 112, No. 5. pp. 802-815.
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AU - Toth, Peter T.

AU - Marsboom, Glenn

AU - Hammel, James M

AU - Chamberlain, Carolyn

AU - Ryan, John J.

AU - Zhang, Hannah J.

AU - Sharp, Willard W.

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AU - Trivedi, Kalyani

AU - Weir, E. Kenneth

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N2 - 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 (<5 minutes) causes mitochondrial fission by a cyclin-dependent kinase- mediated phosphorylation of dynamin-related protein 1 (Drp1) at serine 616. Fission triggers a metabolic shift in the ductal smooth muscle cells that activates pyruvate dehydrogenase and increases mitochondrial H2O2 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.

AB - 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 (<5 minutes) causes mitochondrial fission by a cyclin-dependent kinase- mediated phosphorylation of dynamin-related protein 1 (Drp1) at serine 616. Fission triggers a metabolic shift in the ductal smooth muscle cells that activates pyruvate dehydrogenase and increases mitochondrial H2O2 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.

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