Epigenetic Dysregulation of the Dynamin-Related Protein 1 Binding Partners MiD49 and MiD51 Increases Mitotic Mitochondrial Fission and Promotes Pulmonary Arterial Hypertension

Chen, Kuang‐Hueih; Dasgupta, Asish; Lin, Jie; Potus, François; Bonnet, Sébastien; Iremonger, James; Fu, Jennifer; Mewburn, Jeffrey; Wu, Danchen; Dunham‐Snary, Kimberly J.; Theilmann, Anne L.; Jing, Zhi‐Cheng; Hindmarch, Charles; Ormiston, Mark L.; Lawrie, Allan; Archer, Stephen L.

doi:10.1161/circulationaha.117.031258

Cited by 128 publications

(158 citation statements)

References 51 publications

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“…DRP1 translocation requires interaction with adaptor proteins (121), including the mitochondrial dynamics proteins MiD49 and MiD51. Elevated MiD49 and MiD51 levels in PASMCs from PAH patients led to enhanced DRP1-mediated fission (122). In parallel, decreased MFN2 expression was observed in diseased PASMCs (123) and skeletal muscle (6).…”

Section: Increased Fission and Mitochondrial Fragmentationmentioning

confidence: 90%

Mitochondrial metabolism in pulmonary hypertension: beyond mountains there are mountains

Culley

Chan

2018

Journal of Clinical Investigation

131

110

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Pulmonary hypertension (PH) is a heterogeneous and fatal disease of the lung vasculature, where metabolic and mitochondrial dysfunction may drive pathogenesis. Similar to the Warburg effect in cancer, a shift from mitochondrial oxidation to glycolysis occurs in diseased pulmonary vessels and the right ventricle. However, appreciation of metabolic events in PH beyond the Warburg effect is only just emerging. This Review discusses molecular, translational, and clinical concepts centered on the mitochondria and highlights promising, controversial, and challenging areas of investigation. If we can move beyond the "mountains" of obstacles in this field and elucidate these fundamental tenets of pulmonary vascular metabolism, such work has the potential to usher in much-needed diagnostic and therapeutic approaches for the mitochondrial and metabolic management of PH.

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Section: Increased Fission and Mitochondrial Fragmentationmentioning

confidence: 90%

Mitochondrial metabolism in pulmonary hypertension: beyond mountains there are mountains

Culley

Chan

2018

Journal of Clinical Investigation

131

110

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“…Then, we found that the PAH group was most positively correlated with enriched gene sets like transcription elongation factor complex, inclusion body, and axon cytoplasm while compared with the control group. Kuanghueih Chen et al indicated that transcription elongation factor complex might be involved in the pathogenesis of PAH [ 15 ]. Besides, we identified 150 DEGs between the PAH patients and normal control based on two mRNA microarray data sets.…”

Section: Discussionmentioning

confidence: 99%

Identification of novel biomarkers involved in pulmonary arterial hypertension based on multiple-microarray analysis

Chen

Feng

et al. 2020

Bioscience Reports

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Pulmonary arterial hypertension (PAH) is a life-threatening chronic cardiopulmonary disorder. However, studies providing PAH-related gene expression profiles are scarce. To identify hub genes involved in PAH, we investigate two microarray data sets from gene expression omnibus (GEO). A total of 150 differentially expressed genes (DEGs) were identified by limma package. Enriched Gene Ontology (GO) annotations and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of DEGs mostly included mitotic nuclear division, ATPase activity, and Herpes simplex virus one infection. Ten hub genes from three significant modules were ascertained by Cytoscape (CytoHubba). Gene set enrichment analysis (GSEA) plots showed that transcription elongation factor complex was the most significantly enriched gene set positively correlated with the PAH group. At the same time, solute proton symporter activity was the most significantly enriched gene set positively correlated with the control group. Correlation analysis between hub genes suggested that SMC4, TOP2A, SMC2, KIF11, KIF23, ANLN, ARHGAP11A, SMC3, SMC6 and RAD50 may involve in the pathogenesis of PAH. Then, the miRNA-target genes regulation network was performed to unveil the underlying complex association among them. Finally, RNA extracted from monocrotaline (MCT)-induced Rat-PAH model lung artery tissues were to conduct quantitative real-time PCR (qRT-PCR) to validate these hub genes. In conclusion, our study offers new evidence for the underlying molecular mechanisms of PAH as well as attractive targets for diagnosis and treatment of PAH.

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“…17 Briefly, MFC was calculated as the total mitochondrial number divided by the total mitochondrial area in each confocal microscopy image. 17 The percentage area of each category in each confocal image was calculated and the distribution of these three categories among different treatment groups was compared. Punctate, intermediate, and filamentous mitochondria were classified manually by their morphology initially, followed by the application of a machine-learning algorithm, based on mitochondrial area, length, and sphericity.…”

Section: Mitochondrial Morphology Analysismentioning

confidence: 99%

Identification of novel dynamin‐related protein 1 (Drp1) GTPase inhibitors: Therapeutic potential of Drpitor1 and Drpitor1a in cancer and cardiac ischemia‐reperfusion injury

Dasgupta

Chen

et al. 2019

The FASEB Journal

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Abbreviations: Drp1, dynamin-related protein 1; Drp1 K38A, mutant mouse Drp1 plasmid in which lysine 38 is substituted by alanine; Drp1 WT, wild-type mouse Drp1 plasmid; Drpitor, Drp1 inhibitor; Fis1, mitochondrial fission 1 protein; GMP-PNP, guanosine 5′-[β,γ-imido]triphosphate; HA, hemagglutinin; IC50, half maximal inhibitory concentration; IR, ischemia-reperfusion; mdivi-1, mitochondrial division inhibitor 1; MFC, mitochondrial fragmentation count; MFF, mitochondrial fission factor; MiD49, mitochondrial dynamics protein of 49 kDa; MiD51, mitochondrial dynamics protein of 51 kDa; OMM, outer mitochondrial membrane; ROS, reactive oxygen species; RV, right ventricle; RVEDP, right ventricular end-diastolic pressure; siDrp1, small interfering RNA against Drp1. AbstractMitochondrial fission is important in physiological processes, including coordination of mitochondrial and nuclear division during mitosis, and pathologic processes,

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Epigenetic Dysregulation of the Dynamin-Related Protein 1 Binding Partners MiD49 and MiD51 Increases Mitotic Mitochondrial Fission and Promotes Pulmonary Arterial Hypertension

Abstract: In health, MiDs regulate Drp1-mediated fission, whereas in disease, epigenetic upregulation of MiDs increases mitotic fission, which drives pathological proliferation and apoptosis resistance. The miR-34a-3p-MiD pathway offers new therapeutic targets for PAH.

Cited by 128 publications

References 51 publications

Mitochondrial metabolism in pulmonary hypertension: beyond mountains there are mountains

Mitochondrial metabolism in pulmonary hypertension: beyond mountains there are mountains

Identification of novel biomarkers involved in pulmonary arterial hypertension based on multiple-microarray analysis

Identification of novel dynamin‐related protein 1 (Drp1) GTPase inhibitors: Therapeutic potential of Drpitor1 and Drpitor1a in cancer and cardiac ischemia‐reperfusion injury

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