Abstract 17517: Deficiency of the Iron-Sulfur Scaffold Protein Bola3 Promotes Pulmonary Hypertension by Modulating Mitochondrial and Glycine Metabolism

Background & Hypothesis: Deficiencies of iron-sulfur (Fe-S) clusters have been linked to pulmonary hypertension (PH), a deadly vascular disease with poorly defined molecular origins. BOLA3 regulates Fe-S biogenesis, thus controlling oxidative mitochondrial processes as well as production of lipoic acid, an enzyme moiety critical for glycine biosynthesis. BOLA3 mutations result in multiple mitochondrial dysfunction syndrome, a fatal autosomal recessive disorder that has been associated with PH. However, a molecular role of BOLA3 in PH remains undefined. Methods & Results: In cultured hypoxic pulmonary arterial endothelial cells (PAECs) as well as lung from human and multiple rodent models of PH, endothelial BOLA3 was downregulated and was dependent upon epigenetic histone 3 lysine 9 acetylation of the BOLA3 promoter. Via gain and loss of function analyses of BOLA3 in cultured PAECs, BOLA3 deficiency decreased Fe-S integrity (0.31±0.011-fold, p<0.01), thus altering mitochondrial expression of lipoate-contai...