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.

Mitochondria are essential organelles for energy production, calcium homeostasis, redox signaling, and other cellular responses involved in pulmonary vascular biology and disease processes. Mitochondrial homeostasis depends on a balance in mitochondrial fusion and fission (dynamics). Mitochondrial dynamics are regulated by a viable circadian clock. Hypoxia and nicotine exposure can cause dysfunctions in mitochondrial dynamics, increases in mitochondrial reactive oxygen species generation and calcium concentration, and decreases in ATP production. These mitochondrial changes contribute significantly to pulmonary vascular oxidative stress, inflammatory responses, contractile dysfunction, pathologic remodeling, and eventually pulmonary hypertension. In this review article, therefore, we primarily summarize recent advances in basic, translational, and clinical studies of circadian roles in mitochondrial metabolism in the pulmonary vasculature. This knowledge may not only be crucial to fully understanding the development of pulmonary hypertension, but also greatly help to create new therapeutic strategies for treating this devastating disease and other related pulmonary disorders.

Pulmonary hypertension (PH) is a devastating disease characterized by a progressive increase in pulmonary arterial pressure leading to right ventricular failure and death. A major cellular response in this disease is the contraction of smooth muscle cells (SMCs) of the pulmonary vasculature. Cell contraction is determined by the increase in intracellular Ca²⁺ concentration ([Ca²⁺]_i), which is generated and regulated by various ion channels. Several studies by us and others have shown that ryanodine receptor 2 (RyR2), a Ca²⁺-releasing channel in the sarcoplasmic reticulum (SR), is an essential ion channel for the control of [Ca²⁺]_i in pulmonary artery SMCs (PASMCs), thereby mediating the sustained vasoconstriction seen in PH. FK506-binding protein 12.6 (FKBP12.6) strongly associates with RyR2 to stabilize its functional activity. FKBP12.6 can be dissociated from RyR2 by a hypoxic stimulus to increase channel function and Ca²⁺ release, leading to pulmonary vasoconstriction and PH. More specifically, dissociation of the RyR2–FKBP12.6 complex is a consequence of increased mitochondrial ROS generation mediated by the Rieske iron-sulfur protein (RISP) at the mitochondrial complex III after hypoxia. Overall, RyR2/FKBP12.6 dissociation and the corresponding signaling pathway may be an important factor in the development of PH. Novel drugs and biologics targeting RyR2, FKBP12.6, and related molecules may become unique effective therapeutics for PH.

Type 1 diabetes (T1D) is a serious disease which affects millions of people worldwide and is a major factor for vascular contributions to cognitive impairment and dementia (VCID). In this study, we first characterized cognitive and memory impairments, then evaluated their underlying molecular mechanisms, and finally determined sex-dependent effects in male and female mice with streptozotocin (STZ)-induced T1D. Our findings indicated that significant cognitive impairment, memory loss, and vascular dementia occurred in male and female T1D mice. Cerebral artery (CA) blood flow was greatly reduced in the various brain regions tested. ROS generation in isolated cells, mitochondria, and mitochondrial complex III from CA smooth muscle cells (CASMCs) were all increased in T1D. DNA damage and Tau phosphorylation in CASMCs were largely increased. Linear regression analysis revealed that T1D-induced increased blood glucose was highly correlated with increased ROS production and increased VCID. Taken together, we conclude that T1D causes increased mitochondrial complex III ROS production, DNA damage, and Chk2 phosphorylation in CASMC, thereby leading to vascular dementia in both male and female mice; our results further demonstrate that mitochondrial complex III ROS-mediated DNA damage is more significant in male than female mice, which contributes to more serious vascular dementia in the former than the latter.