Decreased OLA1 (Obg-Like ATPase-1) Expression Drives Ubiquitin-Proteasome Pathways to Downregulate Mitochondrial SOD2 (Superoxide Dismutase) in Persistent Pulmonary Hypertension of the Newborn

摘要

Persistent pulmonary hypertension of the newborn (PPHN) is a failure of pulmonary vascular resistance to declineat birth rapidly. One principal mechanism implicated in PPHN development is mitochondrial oxidative stress. Expressionand activity of mitochondrial SOD2 (superoxide dismutase) are decreased in PPHN; however, the mechanism remainsunknown. Recently, OLA1 (Obg-like ATPase-1) was shown to act as a critical regulator of proteins controlling cellresponse to stress including Hsp70, an obligate chaperone for SOD2. Here, we investigated whether OLA1 is causallylinked to PPHN. Compared with controls, SOD2 expression is reduced in distal-pulmonary arteries (PAs) from patientswith PPHN and fetal-lamb models. Disruptions of the SOD2 gene reproduced PPHN phenotypes, manifested by elevatedright ventricular systolic pressure, PA-endothelial cells apoptosis, and PA-smooth muscle cells proliferation. Analysesof SOD2 protein dynamics revealed higher ubiquitinated-SOD2 protein levels in PPHN-lambs, suggesting dysregulatedprotein ubiquitination. OLA1 controls multiple proteostatic mechanisms and is overexpressed in response to stress. Wedemonstrated that OLA1 acts as a molecular chaperone, and its activity is induced by stress. Strikingly, OLA1 expressionis decreased in distal-PAs from PPHN-patients and fetal-lambs. OLA1 defciency enhanced CHIP affnity for Hsp70-SOD2 complexes, facilitating SOD2 degradation. Consequently, mitochondrial H2O2 formation is impaired, leadingto 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 accountsfor SOD2 downregulation and, therefore, a therapeutic target in PPHN treatments.