Targeting mitoNEET in pulmonary hypertension

Pulmonary hypertension (PH), an increasingly common clinical disorder, causes significant morbidity and mortality. PH is caused by increased pulmonary vascular cell proliferation resulting in pathological remodeling of the pulmonary vascular wall and increased arterial stiffness. Altered mitochondrial and metabolic function drive pulmonary vascular remodeling. This proposal focuses on the role of altered mitochondrial function in patients with PH secondary to lung disease (Group 3 PH). Because current PH therapies are ineffective in Group 3 PH patients, this proposal seeks to identify novel targets and therapies that can reduce mitochondrial and metabolic dysregulation in Group 3 PH. The proposed studies focus on the role of a novel outer mitochondrial membrane protein, mitoNEET (gene cisd1). MitoNEET regulates mitochondrial iron metabolism, bioenergetics, and cellular metabolism through binding and transfer of Fe-S clusters. Preliminary data reveal that mitoNEET expression is increased in pulmonary artery smooth muscle cells (PASMC) and platelets from Group 3 PH patients. Our data show that increases in PASMC mitoNEET are sufficient to induce PASMC proliferation and alterations in mitochondrial function in vitro and cause PH in mice in vivo. Preliminary data further show that selective mitoNEET ligands reverse PASMC derangements in vitro and attenuate PH in vivo. We hypothesize that mitoNEET-mediated mitochondrial iron loading induces mitochondrial dysregulation that promotes PASMC proliferation and that mitoNEET ligands stabilize Fe-S clusters in mitoNEET to reduce mitochondrial iron, metabolic dysregulation, and PASMC proliferation in Group 3 PH. Aim 1 will define how mitoNEET regulates PASMC mitochondrial function and proliferation in vitro using human and rat Group 3 PH PASMC, mitoNEET gain- and loss-of-function approaches, and mitoNEET ligands. These studies will provide new insights into regulation of PASMC proliferation by mitoNEET. Aim 2 will examine alterations in mitoNEET expression and function during PH pathogenesis in vivo using a rat model of Group 3 PH. Dose- and time- ranging studies of mitoNEET ligands will be examined for ability to modulate PH and vascular remodeling in vivo and to reverse PASMC derangements. Aim 3 will test mitoNEET and bioenergetic function in platelets and PASMC from Group 3 PH patients. Platelet mitochondrial function will be assessed before and after ex vivo treatment with mitoNEET ligands. This novel approach could enable further sub-phenotyping / characterization of bioenergetic dysregulation in Group 3 PH patients and permit identification of patients uniquely susceptible to mitoNEET ligands in future clinical trials. The results will provide novel mechanistic understating of mitoNEET in PASMC biology and Group 3 PH pathogenesis and permit new and potentially disease-modifying strategies for targeting aberrant metabolism in PH to reverse disease progression. The study team will leverage their expertise in pulmonary vascular, mitoNEET, bioenergetics and mitochondrial biology, drug development, and clinical trials in PH to ensure the success of the proposed studies. Project Number: 5R01HL175515-02 | Fiscal Year: 2026 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: C HART | Institution: EMORY UNIVERSITY, ATLANTA, GA | Award Amount: $559,740 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1-RCCS-B(03)] View on NIH RePORTER: https://reporter.nih.gov/project-details/5R01HL17551502