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.
Highlights
Mitochondria are important organelles that contribute to cellular homeostasis; the dysregulation of mitochondrial function can lead to cellular or tissue injury, and further systemic affections [1]
PGI2 triggers the synthesis of cyclic adenosine monophosphate and stimulates the peroxisome proliferator activated receptor-γ (PPARγ), leading to an antiproliferative effect in vascular smooth muscle (VSM) cells (VSMCs) [43]
We showed that the dissociation of the FKBP12.6/ryanodine receptor 2 (RyR2) complex causes sarcoplasmic reticulum (SR) Ca2+ leak and increases [Ca2+ ]i in PA smooth muscle cells (PASMCs) (Figure 1), thereby leading to subsequent pulmonary artery remodeling and vasoconstriction
Summary
Mitochondria are important organelles that contribute to cellular homeostasis; the dysregulation of mitochondrial function can lead to cellular or tissue injury, and further systemic affections [1]. Mitochondrial dysfunction due to alterations in ROS production and mitochondrial DNA (mitDNA) damage underlies critical pathophysiological mechanisms in numerous diseases such as diabetes [13,14], fibromyalgia [15], chronic heart failure [16], Alzheimer’s disease [17], chronic kidney disease [18], atherosclerosis [19], and pulmonary hypertension (PH) [5,20]. In this regard, the role of ROS has been extensively investigated in vascular biology. In addition to the generation of ATP and ROS, mitochondria are involved in amino acid metabolism, release of tricarboxylic acid (TCA) cycle metabolites, fatty acid oxidation (FAO) and ketone bodies synthesis [24,25].
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