Important Functions and Molecular Mechanisms of Mitochondrial Redox Signaling in Pulmonary Hypertension

Abstract

Mitochondria are important organelles that act as a primary site to produce reactive oxygen species (ROS). Additionally, mitochondria play a pivotal role in the regulation of Ca2+ signaling, fatty acid oxidation, and ketone synthesis. Dysfunction of these signaling molecules leads to the development of pulmonary hypertension (PH), atherosclerosis, and other vascular diseases. Features of PH include vasoconstriction and pulmonary artery (PA) remodeling, which can result from abnormal proliferation, apoptosis, and migration of PA smooth muscle cells (PASMCs). These responses are mediated by increased Rieske iron–sulfur protein (RISP)-dependent mitochondrial ROS production and increased mitochondrial Ca2+ levels. Mitochondrial ROS and Ca2+ can both synergistically activate nuclear factor κB (NF-κB) to trigger inflammatory responses leading to PH, right ventricular failure, and death. Evidence suggests that increased mitochondrial ROS and Ca2+ signaling leads to abnormal synthesis of ketones, which play a critical role in the development of PH. In this review, we discuss some of the recent findings on the important interactive role and molecular mechanisms of mitochondrial ROS and Ca2+ in the development and progression of PH. We also address the contributions of NF-κB-dependent inflammatory responses and ketone-mediated oxidative stress due to abnormal regulation of mitochondrial ROS and Ca2+ signaling in PH.

In Vitro Cell Death Mechanisms Induced by Dicoma anomala Root Extract in Combination with ZnPcS4 Mediated-Photodynamic Therapy in A549 Lung Cancer Cells

“…The mitochondria is also regarded as the powerhouse of the cell because its function is to synthesize energy molecules in the form of ATP [ 33 ]. The mitochondria also plays a significant role in metabolic pathways such as beta-oxidation, pyruvate decarboxylation, ketogenesis, and apoptosis initiation accomplished via ROS generation and apoptotic proteins activation [ 34 , 35 , 36 ].…”

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

“…One study has shown that phosphorylation and subsequent modulation of NOX activation may be regulated by protein kinase-C (PKC). Our laboratory has also shown that RISP-dependent mitochondrial ROS can activate PKCε and then NOX to induce further ROS generation, i.e., ROS-induced ROS generation (RIRG) [57,67,68]. Importantly, these studies support that mitochondrial ROS generation precedes non-mitochondrial ROS generators, such as NOX [69].…”

Pitfalls of Mitochondrial Redox Signaling Research

“…Redox signals or regulations of mt origin are also implicated in insulin resistance development in peripheral tissues [ 125 , 126 ]. Other listed examples include heart [ 127 , 128 , 129 ] and endothelial pathology [ 130 , 131 , 132 , 133 , 134 ], pulmonary hypertension [ 135 ], sepsis [ 136 ], skeletal muscle injuries (here, mt ROS signal for repair mechanisms, [ 137 , 138 ]), and NLR family pyrin domain-containing 3 (NLRP3)-related inflammatory states [ 139 , 140 , 141 ]. This list is illustrative and incomplete.…”