Nitration-mediated activation of the small GTPase RhoA stimulates cellular glycolysis through enhanced mitochondrial fission

Mitochondrial fission and a Warburg phenotype of increased cellular glycolysis are involved in the pathogenesis of pulmo-nary hypertension (PH). The purpose of this study was to determine whether increases in mitochondrial fission are involved in a glycolytic switch in pulmonary arterial endothe-lial cells (PAECs). Mitochondrial fission is increased in PAEC isolated from a sheep model of PH induced by pulmonary overcirculation (Shunt PAEC). In Shunt PAEC we identified increases in the S616 phosphorylation responsible for dynamin-related protein 1 (Drp1) activation, the mitochondrial redis-tribution of Drp1, and increased cellular glycolysis. Reducing mitochondrial fission attenuated cellular glycolysis in Shunt PAEC. In addition, we observed nitration-mediated activation of the small GTPase RhoA in Shunt PAEC, and utilizing a nitration-shielding peptide, NipR1 attenuated RhoA nitration and reversed the Warburg phenotype. Thus, our data identify a novel link between RhoA, mitochondrial fission, and cellular glycolysis and suggest that targeting RhoA nitration could have therapeutic benefits for treating PH.

Automated summary

This study finds that mitochondrial fission and increased cellular glycolysis are involved in the pathogenesis of pulmonary hypertension. In pulmonary arterial endothelial cells, mitochondrial fission leads to increased cellular glycolysis. By reducing mitochondrial fission, the increased cellular glycolysis can be attenuated. Additionally, a nitration-mediated activation of RhoA is observed, and inhibiting RhoA nitration can reverse the increased cellular glycolysis. Therefore, targeting RhoA nitration could have therapeutic benefits for treating pulmonary hypertension.