Mitochondria-centered signalling in pulmonary hypertension: From metabolic reprogramming to vascular remodeling and right ventricular failure.

Abstract

Pulmonary hypertension (PH) is a progressive cardiopulmonary disorder characterized by pulmonary vascular remodeling, increased pulmonary vascular resistance, and right ventricular failure. Beyond its bioenergetic function, mitochondria act as signalling hubs that integrate metabolic flux, redox homeostasis, calcium handling, organelle contact sites, and cell-death programs. Accumulating evidence indicates that mitochondrial signalling abnormalities contribute to PH by promoting pulmonary artery smooth muscle cell proliferation, endothelial dysfunction, apoptosis resistance, inflammatory activation, and right ventricular metabolic remodeling. In this review, we summarize mitochondria-centered signalling pathways in pulmonary hypertension, with a primary focus on the well-established mechanisms in Group 1 PAH, including HIF-1α/PDK-mediated metabolic reprogramming, ROS-sensitive signalling, Drp1-dependent mitochondrial fission, PINK1/Parkin-mediated mitophagy, and MAM-regulated calcium transfer. Emerging evidence from other PH groups is also discussed where available.