XLOC_010588 Promotes Mitophagy Via BAG2-Mediated PINK1 Stabilization in HPH

BACKGROUND: Pulmonary hypertension (PH) is a severe disorder, with hypoxic PH (HPH) representing a major subtype characterized by elevated pulmonary artery pressure due to chronic hypoxia. Long noncoding RNAs are implicated in various cellular processes, but their role in mitophagy regulation within pulmonary artery smooth muscle cells remains unclear. This study aims to investigate the role of long noncoding RNA XLOC_010588 (XLOC_010588) in modulating mitophagy and HPH pathogenesis. METHODS: We examined the interaction between XLOC_010588 and BAG2 (BCL2-associated athanogene 2), a regulator of PINK1 stability, using molecular and cellular assays. The role of XLOC_010588 in BAG2-mediated PINK1 stabilization and mitophagy activation was assessed in hypoxic pulmonary artery smooth muscle cells. Additionally, the transcriptional regulation of XLOC_010588 by SP1 (specificity protein 1) was investigated. Clinical samples from patients with HPH were analyzed for SP1/BAG2/PINK1 expression, and in vivo experiments were conducted in HPH rats with BAG2 knockdown to evaluate its therapeutic potential. RESULTS: XLOC_010588 was found to bind to BAG2, thereby inhibiting PINK1 ubiquitination and promoting its stabilization on damaged mitochondria. This activation of the PINK1/Parkin pathway increased mitophagy and pulmonary artery smooth muscle cell proliferation. SP1 was identified as a positive regulator of XLOC_010588 expression. Clinically, BAG2 levels were significantly elevated in patients with HPH. In vivo, BAG2 knockdown alleviated HPH in rats, confirming its role in disease progression. CONCLUSIONS: Our study reveals a novel mechanism in which XLOC_010588 promotes mitophagy via BAG2-dependent suppression of PINK1 ubiquitination, contributing to pulmonary artery smooth muscle cell proliferation and HPH development. These findings highlight the potential of targeting the XLOC_010588/BAG2/PINK1 axis for HPH treatment.