Inhibitors of Mitochondrial Dynamics Mediated by Dynamin-Related Protein 1 in Pulmonary Arterial Hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a chronic, lethal pulmonary disease characterized by pulmonary vascular remodeling. It leads to malignant results, such as rupture of pulmonary arterial dissection, dyspnea, right heart failure, and even death. Previous studies have confirmed that one of the main pathological changes of this disease is abnormal mitochondrial dynamics, which include mitochondrial fission, fusion, and autophagy that keep a dynamic balance under certain physiological state. Dynamin-related protein 1 (Drp1), the key molecule in mitochondrial fission, mediates mitochondrial fission while also affecting mitochondrial fusion and autophagy through numerous pathways. There are various abnormalities of Drp1 in PAH pathophysiology, including Drp1 overexpression and activation as well as an upregulation of its outer mitochondrial membrane ligands. These aberrant alterations will eventually induce the development of PAH. With the process of recent studies, the structure and function of Drp1 have been gradually revealed. Meanwhile, inhibitors targeting this pathway have also been discovered. This review aims to shed more light on the mechanism of Drp1 and its inhibitors in the abnormal mitochondrial dynamics of PAH. Furthermore, it seeks to provide more novel insights to clinical therapy.

Targeting Mitochondrial Metabolic Dysfunction in Pulmonary Hypertension: Toward New Therapeutic Approaches?

“…Increased cytoplasmic GTPase dynamin-related protein 1 (DRP1) in pulmonary arterial SMCs, PPAR-γ coactivator (PGC1 α), and HIF-1 are involved in this mechanism [56]. Numerous per-clinical studies have shown that the downregulation of DRP1 by inhibitors can reverse PAH [56][57][58]. Because DRP1 phosphorylation leads to fission, DRP1 activity could be modulated by a variety of kinases.…”

“…Beyond targeting mitochondrial metabolic abnormalities in PAH, therapeutics targeting mitochondrial fission are also promising in animal models. Therapies targeting DRP1 and its binding partners, miD49 and miD51, are under investigation [58]. For example, the inhibition of DRP-1 activity by Mdivi or SiDRP-1 reduces proliferation and induces cell cycle arrest [63].…”

Fatty Oil of Descurainia Sophia Nanoparticles Improve Monocrotaline-Induced Pulmonary Hypertension in Rats Through PLC/IP3R/Ca2+ Signaling Pathway

“… 44 Previous studies have shown that abnormal proliferation of RPASMC cells is the main cause of PH 45 , 46 and abnormal mitochondrial fission and fusion is closely related to abnormal proliferation of RPASMC cells. 47 Mitochondrial fission and fusion is mainly regulated by the mitochondrial dynein protein Drp1 and the mitochondrial fusion-related protein MFN2. MFN2 is located in the mitochondrial outer membrane, which can promote the fusion of two adjacent mitochondria and repair mitochondrial damage.…”

Mitochondrial dysfunction in pulmonary arterial hypertension

“…Mitochondrial fission mainly depends on the dynamin-related protein 1 (DRP1) in the cytoplasm and the proteins on the outer membrane of mitochondria (OMM), such as mitochondrial fission 1 (FIS1), mitochondrial fission factor (MFF), mitochondrial dynamics protein of 49 (MID49) and mitochondrial dynamics protein of 51 (MID51) ( Sabouny and Shutt, 2020 ). DRP1 inhibitor can inhibit the development of PAH by reversing mitochondrial function ( Parra et al, 2017 ; Tian et al, 2018 ; Zhuan et al, 2020 ; Wu et al, 2021 ; Xiao et al, 2022 ). Extracellular regulated kinase, p38 Mitogen-Activated protein kinases (MAPK), camp-dependent protein Kinase, adenosine monophosphate-activated protein kinase and sirtuin can phosphorylate DRP1 ( Ren et al, 2020 ).…”

“…In addition, therapeutic strategies targeting the inhibition of mitochondrial fission have also shown promising therapeutic prospects in animal models, such as dynamin-related protein 1, mitochondrial fission mediators (MiD49M, MiD51), up-regulation of MFN2, etc ( Marsboom et al, 2012 ; Chen K. H. et al, 2018 ; Wu et al, 2019 ; Umezu et al, 2020 ; Feng et al, 2021 ; Xiao et al, 2022 ). Looking forward to the translation of these drugs from the laboratory to the clinic.…”