Mitochondrial Genome‐Encoded lncND5 Regulates Mitophagy in Hypoxic Pulmonary Artery Smooth Muscle Cell

ABSTRACT Long noncoding RNAs (lncRNAs) are implicated in pulmonary hypertension (PH) progression. However, the underlying mechanisms remain largely unknown. Although mitophagy plays a crucial role in hypoxia‐induced PH pathogenesis, the role of lncRNAs in mitophagy remains unclear. Especially, the mechanism of lncRNA encoded by the mitochondrial genome in regulating mitophagy needs to be elucidated. We explored the role of lncND5 in human pulmonary artery smooth muscle cells (PASMCs) and Sugen5416 plus hypoxia (SuHx)‐induced PH mouse model in vitro and in vivo. LncND5 expression and localization were detected using real‐time quantitative polymerase chain reaction (RT‐qPCR) and fluorescence in situ hybridization (FISH). We investigated the molecular mechanism of lncND5 using western blotting, flow cytometry, RNA immunoprecipitation, RNA pulldown, transmission electron microscopy (TEM), immunofluorescence (IF), and echocardiography. Mitochondrial lncND5 expression was decreased under hypoxia in human PASMCs. Mechanistically, in the mitochondria, lncND5 maintains complex I activity by binding with mitochondrial ADH‐ubiquinone oxidoreductase chain 5 (MT‐ND5) at nucleotides 1086–1159 bp, thereby regulating mitochondrial reactive oxygen species (mROS) release and alleviating mitophagy. Additionally, lncND5 regulates mitophagy via cardiolipin (CL), which regulates complex I activity, inhibiting ROS release then relieving mitophagy. In the cytoplasm, lncND5 inhibits mitophagy by directly interacting with hydroxymethylglutaryl‐CoA synthase 1 (HMGCS1). Notably, lncND5 is transported from the mitochondria to the cytoplasm and is mediated by TAR DNA‐binding protein 43 (TDP‐43). Our findings, for the first time, reveal that lncND5 may be a potential therapeutic approach for PH.