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.