LONP1 facilitates pulmonary artery smooth muscle cell glycolytic reprogramming by degrading MPC1 in pulmonary hypertension

Pulmonary hypertension (PH) is a chronic and life-threatening disease characterized by pulmonary vascular remodeling (PVR), which involves the abnormal proliferation of pulmonary artery smooth muscle cells (PASMCs). These cells exhibit metabolic characteristics akin to Cancer cells, particularly in their shift toward glycolysis. The Lon protease 1 (LONP1) has been shown to promote glycolytic reprogramming of tumor cells, conferring a malignant proliferative phenotype. However, the precise role of LONP1 in PH remains unclear. In the present study, Su5416/hypoxia-induced and monocrotaline (MCT)-induced PH rodent models and platelet-derived growth factor BB (PDGF-BB)-induced PASMCs were used to investigate the role and mechanism of LONP1 in PH. The results revealed an up-regulation of LONP1 expression in lung tissues from two PH rodent models, as well as in PDGF-BB-induced PASMCs. In vivo knockdown of LONP1 significantly alleviated PASMC mitochondrial dysfunction, reduced glycolytic enzyme expression, and decreased lactate accumulation, thereby mitigating PVR. Additionally, in vitro experiments demonstrated that knockdown or inhibition of LONP1 attenuated glycolytic reprogramming, proliferation, and migration of PASMCs, whereas overexpression of LONP1 had converse effects. Mechanistic studies confirmed that mitochondrial pyruvate carrier 1 (MPC1) was a direct substrate for LONP1-mediated degradation. Functional experiments with MPC1 knockdown and overexpression further elucidated its role in the proliferation and migration of PASMCs. Rescue experiments indicated that MPC1 knockdown abrogated the suppressive effects of LONP1 knockdown on glycolytic reprogramming, proliferation, and migration in PASMCs. Therapeutically, knockdown or pharmacological inhibition of LONP1 significantly reversed MCT-induced PH in rats. Thus, targeting LONP1 may represent a promising therapeutic strategy for PH.

Lon protease 1; glycolytic reprogramming; mitochondrial pyruvate carrier 1; pulmonary hypertension; pulmonary vascular remodeling.