Mitochondrial Dysfunction in Pulmonary Hypertension

Ryanto, Gusty Rizky Teguh; Suraya, Ratoe; Nagano, Tatsuya

doi:10.3390/antiox12020372

Cited by 8 publications

(6 citation statements)

References 94 publications

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“…Mitochondrial dysfunction is known to play a crucial role in metabolic reprogramming. 18 In this study, we present evidence that CH-PH induces mitochondrial disorder through the activation of NOX1/4-TRPM2, resulting in increased mitochondrial ROS production, elevated MMP, mtDNA damage, accumulation of mitochondrial Ca 2+ , reduced mtDNA copy number, and enhanced mitochondrial fission. The complex mechanism by which NOX1/4-TRPM2 regulates mitochondrial dysfunction requires further investigation, and we propose 3 possible mechanisms.…”

Section: Discussionmentioning

confidence: 68%

“…17 This phenomenon of metabolic dysregulation, known as the Warburg effect or aerobic glycolysis, is commonly found in tumor cells. 18 Our recent study found that PAH induces metabolic reprogramming in PASMCs via CircSMOC1 (CircRNA SPARC related modular calcium binding 1)/PTBP1 (polypyrimidine tract-binding protein 1) and CircSMOC1/miR-329-3p to meet the metabolic requirements for cell proliferation. 19 It is unclear whether similar metabolic reprogramming exists in CASMCs of PH.…”

Section: Nonstandard Abbreviations and Acronymsmentioning

confidence: 99%

“…Mitochondrial dysfunction is associated with metabolic reprogramming. 18 We examined the effects of CH and NOX1/4-TRPM2 signaling axis on mitochondrial ROS production, the mitochondrial membrane potential (MMP), mitochondrial DNA (mtDNA) copy number, mitochondrial Ca 2+ , and mitochondrial dynamics in CASMCs. Increased mitochondrial ROS production, elevated MMP levels, decreased mtDNA copy number, and mitochondrial Ca 2+ overload were observed in CH-CASMCs.…”

Section: Nox1/4-trpm2 Signal Axis Mediated Mitochondrial Dysfunctionmentioning

confidence: 99%

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Pulmonary Hypertension Induces Serotonin Hyperreactivity and Metabolic Reprogramming in Coronary Arteries via NOX1/4-TRPM2 Signaling Pathway

Huang,

Wu,

et al. 2024

Hypertension

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BACKGROUND: Clinical evidence revealed abnormal prevalence of coronary artery (CA) disease in patients with pulmonary hypertension (PH). The mechanistic connection between PH and CA disease is unclear. Serotonin (5-hydroxytryptamine), reactive oxygen species, and Ca 2+ signaling have been implicated in both PH and CA disease. Our recent study indicates that NOXs (NADPH oxidases) and TRPM2 (transient receptor potential cation channel subfamily M member 2) are key components of their interplay. We hypothesize that activation of the NOX-TRPM2 pathway facilitates the remodeling of CA in PH. METHODS: Left and right CAs from chronic hypoxia and monocrotaline-induced PH rats were collected to study vascular reactivity, gene expression, metabolism, and mitochondrial function. Inhibitors or specific siRNA were used to examine the pathological functions of NOX1/4-TRPM2 in CA smooth muscle cells. RESULTS: Significant CA remodeling and 5-hydroxytryptamine hyperreactivity in the right CA were observed in PH rats. NOX1/4-mediated reactive oxygen species production coupled with TRPM2-mediated Ca 2+ influx contributed to 5-hydroxytryptamine hyperresponsiveness. CA smooth muscle cells from chronic hypoxia-PH rats exhibited increased proliferation, migration, apoptosis, and metabolic reprogramming in an NOX1/4-TRPM2–dependent manner. Furthermore, the NOX1/4-TRPM2 pathway participated in mitochondrial dysfunction, involving mitochondrial DNA damage, reactive oxygen species production, elevated mitochondrial membrane potential, mitochondrial Ca 2+ accumulation, and mitochondrial fission. In vivo knockdown of NOX1/4 alleviated PH and suppressed CA remodeling in chronic hypoxia rats. CONCLUSIONS: PH triggers an increase in 5-hydroxytryptamine reactivity in the right CA and provokes metabolic reprogramming and mitochondrial disruption in CA smooth muscle cells via NOX1/4-TRPM2 activation. This signaling pathway may play an important role in CA remodeling and CA disease in PH.

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Section: Discussionmentioning

confidence: 68%

Section: Nonstandard Abbreviations and Acronymsmentioning

confidence: 99%

Section: Nox1/4-trpm2 Signal Axis Mediated Mitochondrial Dysfunctionmentioning

confidence: 99%

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Pulmonary Hypertension Induces Serotonin Hyperreactivity and Metabolic Reprogramming in Coronary Arteries via NOX1/4-TRPM2 Signaling Pathway

Huang,

Wu,

et al. 2024

Hypertension

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“…Any disruptions in these functions are collectively termed mitochondrial dysfunction. Several mechanisms of mitochondrial dysfunction have been linked to the development of PH 28,29 . But, the role of MRGs in PH remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Exploration of mitochondrial-related biomarkers and regulatory mechanisms in pulmonary hypertension

Hao,

Wu,

Zhao

et al. 2024

Preprint

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Multiple mechanisms of mitochondrial dysfunction have been implicated in the pathogenesis of pulmonary hypertension (PH). Thus, this study aims to identify biomarkers associated with mitochondrial-related genes (MRGs) in patients with PH. The GSE33463 (blood training set), GSE15197 (tissue training set), GSE113439 (external validation set) and MRGs were all acquired from public databases. Differential expression analysis was undertaken to selected differentially expressed genes (DEGs) from blood and tissue training set, respectively. Then, the DEGs were intersected with MRGs to identify potential candidate genes, followed by detecting their functions via enrichment analysis. Moreover, crucial genes were obtained by overlapping the signature genes from least absolute shrinkage and selection operator (LASSO) regression and support vector machine recursive feature elimination (SVM-RFE). Based on the receiver operating characteristic (ROC) curves of crucial genes, the genes with area under curves (AUC) value ≥ 0.7 were deemed as biomarkers. Gene Set Enrichment Analysis (GSEA), multiple regulatory networks and drug prediction were applied to explore biomarkers’ molecular mechanism. A total of 144 DEGs (78 up-DEGs and 66 down-DEGs) were obtained by intersecting 751 DEGs1 in blood training set and 6,155 DEGs2 in tissue training set. Next, taking the intersection of 144 DEGs and 1,136 MRGs, 7 candidate genes (ALAS2, CPT2, TST, SLC25A39, COQ10B, MRPS30 and MCL1) were acquired and enriched in multiple mitochondria related pathways, like mitochondrial inner membrane. MRPS30, ALAS2 and TST were recognized as biomarkers depending on the 4 crucial genes (CPT2, MRPS30, ALAS2 and TST) through overlapping signature genes by two machine learning algorithms. The immune analysis showed that the percentage of 7 kinds of immune cells (e.g. B cells naive, monocytes, neutrophils) were differed markedly at control and PH groups, and monocytes were related to all three biomarkers. In 3 datasets, the expression of ALAS2 was up-regulated in PH, while MRPS30 was down-regulated in PH. And bisphenol A was predicted by ALAS2, MRPS30 and TST. Three biomarkers (ALAS2, MRPS30 and TST) associated with MRGs was identified and verified, which provided a new perspective to probe the mechanism of MRGs in PH.

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“…Mitochondrial dysfunction/damage significantly contributes to many cardiovascular diseases, including PH [38,[43][44][45][46][47][48]. Previously, we and others have reported that Mfn2 levels are decreased, which correlates with fragmented mitochondria in both animal models and humans with PH [49][50][51].…”

Section: Introductionmentioning

confidence: 88%

Novel Relationship between Mitofusin 2-Mediated Mitochondrial Hyperfusion, Metabolic Remodeling, and Glycolysis in Pulmonary Arterial Endothelial Cells

Yegambaram,

Sun,

Flores

et al. 2023

IJMS

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The disruption of mitochondrial dynamics has been identified in cardiovascular diseases, including pulmonary hypertension (PH), ischemia-reperfusion injury, heart failure, and cardiomyopathy. Mitofusin 2 (Mfn2) is abundantly expressed in heart and pulmonary vasculature cells at the outer mitochondrial membrane to modulate fusion. Previously, we have reported reduced levels of Mfn2 and fragmented mitochondria in pulmonary arterial endothelial cells (PAECs) isolated from a sheep model of PH induced by pulmonary over-circulation and restoring Mfn2 normalized mitochondrial function. In this study, we assessed the effect of increased expression of Mfn2 on mitochondrial metabolism, bioenergetics, reactive oxygen species production, and mitochondrial membrane potential in control PAECs. Using an adenoviral expression system to overexpress Mfn2 in PAECs and utilizing 13C labeled substrates, we assessed the levels of TCA cycle metabolites. We identified increased pyruvate and lactate production in cells, revealing a glycolytic phenotype (Warburg phenotype). Mfn2 overexpression decreased the mitochondrial ATP production rate, increased the rate of glycolytic ATP production, and disrupted mitochondrial bioenergetics. The increase in glycolysis was linked to increased hypoxia-inducible factor 1α (HIF-1α) protein levels, elevated mitochondrial reactive oxygen species (mt-ROS), and decreased mitochondrial membrane potential. Our data suggest that disrupting the mitochondrial fusion/fission balance to favor hyperfusion leads to a metabolic shift that promotes aerobic glycolysis. Thus, therapies designed to increase mitochondrial fusion should be approached with caution.

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Mitochondrial Dysfunction in Pulmonary Hypertension

Cited by 8 publications

References 94 publications

Pulmonary Hypertension Induces Serotonin Hyperreactivity and Metabolic Reprogramming in Coronary Arteries via NOX1/4-TRPM2 Signaling Pathway

Pulmonary Hypertension Induces Serotonin Hyperreactivity and Metabolic Reprogramming in Coronary Arteries via NOX1/4-TRPM2 Signaling Pathway

Exploration of mitochondrial-related biomarkers and regulatory mechanisms in pulmonary hypertension

Novel Relationship between Mitofusin 2-Mediated Mitochondrial Hyperfusion, Metabolic Remodeling, and Glycolysis in Pulmonary Arterial Endothelial Cells

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