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

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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-containing 2-oxoacid dehydrogenases and respiratory chain complexes with consequent control over glycolysis and mitochondrial respiration (extracellular acidification rate 1.83-fold change ± 0.021, p<0.01; oxygen consumption rate 1.26-fold change ± 0.019, p<0.05). In addition, BOLA3 deficiency downregulated the glycine cleavage system protein H (GCSH), thus increasing intracellular glycine content. As a result, BOLA3 deficiency and the resulting increase of glycine increased endothelial proliferation, survival, and vasoconstriction, while decreasing angiogenic potential. In vivo, pharmacologic knockdown of endothelial BOLA3 in normoxic mice increased pulmonary vascular remodeling and right ventricular systolic pressure (BOLA3 knockdown, 24.0±0.43 mmHg vs. siRNA control, 20.4±0.39 mmHg, p<0.01).

Conclusion: BOLA3 acts as a crucial lynchpin connecting Fe-S-dependent oxidative respiration and glycine biology to endothelial metabolic re-programming critical to PH pathogenesis. These results emphasize the complexity of Fe-S-specific metabolic dysfunction in endothelial cells and PH, thus guiding our future endeavors to develop novel Fe-S-dependent diagnostics and therapeutics in this deadly disease.

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