The Potential Important Role of Mitochondrial Rieske Iron–Sulfur Protein as a Novel Therapeutic Target for Pulmonary Hypertension in Chronic Obstructive Pulmonary Disease

Abstract

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide, which is often due to pulmonary hypertension (PH). The underlying molecular mechanisms are poorly understood, and current medications are neither specific nor always effective. In this review, we highlight the recent findings on the roles of altered mitochondrial bioenergetics in PH in COPD. We also discuss the central role of mitochondrial reactive oxygen species (ROS) generation mediated by Rieske iron–sulfur protein (RISP) and review the contributions of RISP-dependent DNA damage and NF-κB-associated inflammatory signaling. Finally, the potential importance of mitochondrial RISP and its associated molecules as novel therapeutic targets for PH in COPD are meticulously discussed.

Mitochondrial Regulation of the Hypoxia-Inducible Factor in the Development of Pulmonary Hypertension

“…Evidence on the importance of ETC proteins in ROS generation comes from in vivo studies of mice with PASMCs-specific conditional deletion of the Rieske iron-sulfur protein (RISP), a protein of the mitochondrial ETC Complex III. These mice showed significantly reduced generation of mtROS and inhibition of calcium ion influx in response to hypoxia [ 80 , 81 ]. Nevertheless, in vitro treatment with H 2 O 2 of pulmonary arteries isolated from these mice resulted in concentration-dependent contractions, confirming that mtROS plays a role in acute hypoxia-induced vasoconstriction [ 81 ].…”

“…However, using available non-selective antioxidants may impact the tricky balance that promotes homeostatic redox signaling or causes detrimental oxidative stress. As a result, mitochondria-targeted compounds that inhibit specific molecules implicated in ROS generation, such as RISP in complex III, may present successful PH treatments [ 80 ].…”