Figure 8.

Schematic representation of enhanced mitochondrial fission–mediated glycolysis through nitration-mediated activation of RhoA. The increased cellular glycolysis (Warburg effect) in pulmonary hypertension (PH) is driven by increased Drp1-mediated mitochondrial fission and enhanced HIF-1α signaling. Drp1 is activated by phosphorylation at S616. Blocking Drp1 activity (Mdivi-1) or stimulating fusion (MFN2 overexpression) reduces aerobic glycolysis. Drp1 S616 phosphorylation is stimulated by the nitration-mediated activation of RhoA due to increased endothelial nitric oxide synthase uncoupling. Blocking the nitration of RhoA with NipR1 reduces Drp1 activity in PH pulmonary arterial endothelial cells; this decreases aerobic glycolysis and reverses the metabolic reprogramming.