Decreased OLA1 (Obg-Like ATPase-1) Expression Drives Ubiquitin-Proteasome Pathways to Downregulate Mitochondrial SOD2 (Superoxide Dismutase) in Persistent Pulmonary Hypertension of the Newborn.
Persistent pulmonary hypertension of the newborn (PPHN) is a failure of pulmonary vascular resistance to decline at birth rapidly. One principal mechanism implicated in PPHN development is mitochondrial oxidative stress. Expression and activity of mitochondrial SOD2 (superoxide dismutase) are decreased in PPHN; however, the mechanism remains unknown. Recently, OLA1 (Obg-like ATPase-1) was shown to act as a critical regulator of proteins controlling cell response to stress including Hsp70, an obligate chaperone for SOD2. Here, we investigated whether OLA1 is causally linked to PPHN. Compared with controls, SOD2 expression is reduced in distal-pulmonary arteries (PAs) from patients with PPHN and fetal-lamb models. Disruptions of the SOD2 gene reproduced PPHN phenotypes, manifested by elevated right ventricular systolic pressure, PA-endothelial cells apoptosis, and PA-smooth muscle cells proliferation. Analyses of SOD2 protein dynamics revealed higher ubiquitinated-SOD2 protein levels in PPHN-lambs, suggesting dysregulated protein ubiquitination. OLA1 controls multiple proteostatic mechanisms and is overexpressed in response to stress. We demonstrated that OLA1 acts as a molecular chaperone, and its activity is induced by stress. Strikingly, OLA1 expression is decreased in distal-PAs from PPHN-patients and fetal-lambs. OLA1 deficiency enhanced CHIP affinity for Hsp70-SOD2 complexes, facilitating SOD2 degradation. Consequently, mitochondrial H2O2 formation is impaired, leading to XIAP (X-linked inhibitor of apoptosis) overexpression that suppresses caspase activity in PA-smooth muscle cells, allowing them to survive and proliferate, contributing to PA remodeling. In-vivo, ola1-/- downregulated SOD2 expression, induced distal-PA remodeling, and right ventricular hypertrophy. We conclude that decreased OLA1 expression accounts for SOD2 downregulation and, therefore, a therapeutic target in PPHN treatments.
['Schultz|Adam|A|', 'Olorundami|Olubunmi A|OA|', 'Teng|Ru-Jeng|RJ|', 'Jarzembowski|Jason|J|', 'Shi|Zheng-Zheng|ZZ|', 'Kumar|Suresh N|SN|', 'Pritchard|Kirkwood|K|', 'Konduri|Girija G|GG|', 'Afolayan|Adeleye J|AJ|']
D000251:Adenosine Triphosphatases D000818:Animals D017209:Apoptosis D015536:Down-Regulation D005260:Female D019204:GTP-Binding Proteins D006439:Hemodynamics D006801:Humans D006861:Hydrogen Peroxide D007231:Infant, Newborn D008168:Lung D008297:Male D008928:Mitochondria D018384:Oxidative Stress D010547:Persistent Fetal Circulation Syndrome D046988:Proteasome Endopeptidase Complex D017382:Reactive Oxygen Species D012756:Sheep D013482:Superoxide Dismutase D025801:Ubiquitin D051636:X-Linked Inhibitor of Apoptosis Protein
oxidative stress apoptosis caspase hypoxemia mitochondria reactive oxygen species