Mitochondria-derived Vesicle Packaging as a Novel Therapeutic Mechanism in Pulmonary Hypertension

Increasing evidence suggests that mitochondrial dysfunction in pulmonary endothelial cells (ECs) plays a causative role in the initiation and progression of pulmonary hypertension (PH); how mitochondria become dysfunctional in PH remains elusive. Mitochondria-derived vesicles (MDVs) are small subcellular vesicles that excise from mitochondria. Whether or not MDVs deregulation causes mitochondrial dysfunction in PH is unknown. This aim of this study was to determine MDVs regulation in ECs and to elucidate how MDVs deregulation in ECs leads to PH. MDVs formation and mitochondrial morphology/dynamics were examined in ECs of the EC-specific-Liver kinase B1 (LKB1) knock out mice (LKB1ec-/-), in monocrotaline (MCT)-induced PH rats, and in lungs of patients with PH. Pulmonary ECs of PH patients and hypoxia-treated pulmonary ECs exhibited increased mitochondrial fragmentation and disorganized mitochondrial ultrastructure characterized by electron lucent-swelling matrix compartments and concentric layering of cristae network, along with defective MDVs shedding. MDVs actively regulated mitochondrial membrane dynamics and mitochondrial ultrastructure via its removing mitofission-related cargoes. The shedding of MDVs from parental mitochondria required LKB1-mediated mitochondrial recruitment of Rab9 GTPase. LKB1ec-/- mice spontaneously developed PH with decreased mitochondrial pools of Rab9 GTPase, defective MDVs shedding, and disequilibrium of mitochondrial fusion-fission cycle in pulmonary ECs. Aerosol intra-tracheal delivery of adeno-associated virus LKB1 reversed PH, along with improved MDVs shedding and mitochondrial functions in rats in vivo. We conclude that LKB1 regulates MDVs shedding and mitochondrial dynamics in pulmonary ECs by enhancing mitochondrial recruitment of Rab9 GTPase. Defect of LKB1-mediated MDVs shedding from parental mitochondria instigates ECs dysfunction and PH.