{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T15:09:34Z","timestamp":1789657774059,"version":"4.0.1"},"reference-count":90,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2023,12,15]],"date-time":"2023-12-15T00:00:00Z","timestamp":1702598400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Institutes of Health, USA","doi-asserted-by":"publisher","award":["HL60190"],"award-info":[{"award-number":["HL60190"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Institutes of Health, USA","doi-asserted-by":"publisher","award":["HL137282"],"award-info":[{"award-number":["HL137282"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Institutes of Health, USA","doi-asserted-by":"publisher","award":["HL134610"],"award-info":[{"award-number":["HL134610"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Institutes of Health, USA","doi-asserted-by":"publisher","award":["HL142212"],"award-info":[{"award-number":["HL142212"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Institutes of Health, USA","doi-asserted-by":"publisher","award":["U01ES033265"],"award-info":[{"award-number":["U01ES033265"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Institutes of Health, USA","doi-asserted-by":"publisher","award":["HL146369"],"award-info":[{"award-number":["HL146369"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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 1\u03b1 (HIF-1\u03b1) 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.<\/jats:p>","DOI":"10.3390\/ijms242417533","type":"journal-article","created":{"date-parts":[[2023,12,15]],"date-time":"2023-12-15T11:26:52Z","timestamp":1702639612000},"page":"17533","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Novel Relationship between Mitofusin 2-Mediated Mitochondrial Hyperfusion, Metabolic Remodeling, and Glycolysis in Pulmonary Arterial Endothelial Cells"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4561-8608","authenticated-orcid":false,"given":"Manivannan","family":"Yegambaram","sequence":"first","affiliation":[{"name":"Center for Translational Science, Florida International University, 11350 SW Village Parkway, Port St. Lucie, FL 34987-2352, USA"},{"name":"Department of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work, Florida International University, Miami, FL 33199, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xutong","family":"Sun","sequence":"additional","affiliation":[{"name":"Center for Translational Science, Florida International University, 11350 SW Village Parkway, Port St. Lucie, FL 34987-2352, USA"},{"name":"Department of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work, Florida International University, Miami, FL 33199, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandro Garcia","family":"Flores","sequence":"additional","affiliation":[{"name":"Center for Translational Science, Florida International University, 11350 SW Village Parkway, Port St. Lucie, FL 34987-2352, USA"},{"name":"Department of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work, Florida International University, Miami, FL 33199, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Lu","sequence":"additional","affiliation":[{"name":"Center for Translational Science, Florida International University, 11350 SW Village Parkway, Port St. Lucie, FL 34987-2352, USA"},{"name":"Department of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work, Florida International University, Miami, FL 33199, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamie","family":"Soto","sequence":"additional","affiliation":[{"name":"Center for Translational Science, Florida International University, 11350 SW Village Parkway, Port St. Lucie, FL 34987-2352, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaime","family":"Richards","sequence":"additional","affiliation":[{"name":"Center for Translational Science, Florida International University, 11350 SW Village Parkway, Port St. Lucie, FL 34987-2352, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7192-1569","authenticated-orcid":false,"given":"Saurabh","family":"Aggarwal","sequence":"additional","affiliation":[{"name":"Department of Cellular Biology & Pharmacology, Howard Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Wang","sequence":"additional","affiliation":[{"name":"Center for Translational Science, Florida International University, 11350 SW Village Parkway, Port St. Lucie, FL 34987-2352, USA"},{"name":"Department of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work, Florida International University, Miami, FL 33199, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiwei","family":"Gu","sequence":"additional","affiliation":[{"name":"Center for Translational Science, Florida International University, 11350 SW Village Parkway, Port St. Lucie, FL 34987-2352, USA"},{"name":"Department of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work, Florida International University, Miami, FL 33199, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9740-405X","authenticated-orcid":false,"given":"Jeffrey R.","family":"Fineman","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of California San Francisco, San Francisco, CA 94143, USA"},{"name":"Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA 94143, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen M.","family":"Black","sequence":"additional","affiliation":[{"name":"Center for Translational Science, Florida International University, 11350 SW Village Parkway, Port St. Lucie, FL 34987-2352, USA"},{"name":"Department of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work, Florida International University, Miami, FL 33199, USA"},{"name":"Department of Cellular Biology & Pharmacology, Howard Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1146\/annurev-physiol-031620-123956","article-title":"Metabolism in Pulmonary Hypertension","volume":"83","author":"Xu","year":"2021","journal-title":"Annu. Rev. Physiol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Pokharel, M.D., Marciano, D.P., Fu, P., Franco, M.C., Unwalla, H., Tieu, K., Fineman, J.R., Wang, T., and Black, S.M. (2023). Metabolic reprogramming, oxidative stress, and pulmonary hypertension. Redox Biol., 64.","DOI":"10.1016\/j.redox.2023.102797"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3704","DOI":"10.1172\/JCI120847","article-title":"Mitochondrial metabolism in pulmonary hypertension: Beyond mountains there are mountains","volume":"128","author":"Culley","year":"2018","journal-title":"J. Clin. Investig."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Sun, X., Lu, Q., Yegambaram, M., Kumar, S., Qu, N., Srivastava, A., Wang, T., Fineman, J.R., and Black, S.M. (2020). TGF-\u03b21 attenuates mitochondrial bioenergetics in pulmonary arterial endothelial cells via the disruption of carnitine homeostasis. Redox Biol., 36.","DOI":"10.1016\/j.redox.2020.101593"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Liang, S., Yegambaram, M., Wang, T., Wang, J., Black, S.M., and Tang, H. (2022). Mitochondrial Metabolism, Redox, and Calcium Homeostasis in Pulmonary Arterial Hypertension. Biomedicines, 10.","DOI":"10.3390\/biomedicines10020341"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1002\/jemt.1070270303","article-title":"Dynamics of mitochondria in living cells: Shape changes, dislocations, fusion, and fission of mitochondria","volume":"27","year":"1994","journal-title":"Microsc. Res. Tech."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1515\/BC.2007.110","article-title":"Molecular machinery of mitochondrial dynamics in yeast","volume":"388","author":"Merz","year":"2007","journal-title":"Biol. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"293893","DOI":"10.1155\/2013\/293893","article-title":"Mitochondrial Fusion Proteins and Human Diseases","volume":"2013","author":"Ranieri","year":"2013","journal-title":"Neurol. Res. Int."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Su\u00e1rez-Rivero, J.M., Villanueva-Paz, M., de la Cruz-Ojeda, P., de la Mata, M., Cot\u00e1n, D., Oropesa-\u00c1vila, M., de Lavera, I., \u00c1lvarez-C\u00f3rdoba, M., Luz\u00f3n-Hidalgo, R., and S\u00e1nchez-Alc\u00e1zar, J.A. (2016). Mitochondrial Dynamics in Mitochondrial Diseases. Diseases, 5.","DOI":"10.3390\/diseases5010001"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1007\/164_2016_38","article-title":"Mitochondrial Fission in Human Diseases","volume":"240","author":"Serasinghe","year":"2017","journal-title":"Handb. Exp. Pharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"654785","DOI":"10.3389\/fnins.2021.654785","article-title":"Mitochondrial Dynamics: A Key Role in Neurodegeneration and a Potential Target for Neurodegenerative Disease","volume":"15","author":"Yang","year":"2021","journal-title":"Front. Neurosci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3258","DOI":"10.1093\/eurheartj\/ehu436","article-title":"Mitochondrial injury and dysfunction in hypertension-induced cardiac damage","volume":"35","author":"Eirin","year":"2014","journal-title":"Eur. Heart J."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"18","DOI":"10.21037\/atm.2018.06.21","article-title":"Mitochondria and cardiovascular diseases\u2014From pathophysiology to treatment","volume":"6","author":"Siasos","year":"2018","journal-title":"Ann. Transl. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1007\/s11906-017-0710-9","article-title":"Role of Mitochondrial Dysfunction in Hypertension and Obesity","volume":"19","author":"Lahera","year":"2017","journal-title":"Curr. Hypertens. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1161\/HYPERTENSIONAHA.120.14686","article-title":"Mitochondrial Fission Mediates Endothelial Inflammation","volume":"76","author":"Forrester","year":"2020","journal-title":"Hypertension"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Kurakula, K., Smolders, V., Tura-Ceide, O., Jukema, J.W., Quax, P.H.A., and Goumans, M.J. (2021). Endothelial Dysfunction in Pulmonary Hypertension: Cause or Consequence?. Biomedicines, 9.","DOI":"10.3390\/biomedicines9010057"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1186\/1465-9921-10-95","article-title":"Endothelial cells and pulmonary arterial hypertension: Apoptosis, proliferation, interaction and transdifferentiation","volume":"10","author":"Sakao","year":"2009","journal-title":"Respir. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"R393","DOI":"10.1152\/ajpregu.00584.2012","article-title":"Mitochondrial morphology transitions and functions: Implications for retrograde signaling?","volume":"304","author":"Martin","year":"2013","journal-title":"Am. J. Physiol. -Regul. Integr. Comp. Physiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"26185","DOI":"10.1074\/jbc.M503062200","article-title":"Disruption of fusion results in mitochondrial heterogeneity and dysfunction","volume":"280","author":"Chen","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1042\/BST20190987","article-title":"Mitochondrial hyperfusion: A friend or a foe","volume":"48","author":"Das","year":"2020","journal-title":"Biochem. Soc. Trans."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2827","DOI":"10.1016\/j.celrep.2018.02.055","article-title":"The PERK Arm of the Unfolded Protein Response Regulates Mitochondrial Morphology during Acute Endoplasmic Reticulum Stress","volume":"22","author":"Lebeau","year":"2018","journal-title":"Cell Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1038\/emboj.2009.89","article-title":"SLP-2 is required for stress-induced mitochondrial hyperfusion","volume":"28","author":"Tondera","year":"2009","journal-title":"Embo J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1242\/jcs.114.5.867","article-title":"Control of mitochondrial morphology by a human mitofusin","volume":"114","author":"Santel","year":"2001","journal-title":"J. Cell Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"6535","DOI":"10.1242\/jcs.01565","article-title":"Mitofusin 1 and 2 play distinct roles in mitochondrial fusion reactions via GTPase activity","volume":"117","author":"Ishihara","year":"2004","journal-title":"J. Cell Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2966","DOI":"10.1038\/sj.emboj.7601184","article-title":"Regulation of mitochondrial morphology through proteolytic cleavage of OPA1","volume":"25","author":"Ishihara","year":"2006","journal-title":"Embo J."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1113\/jphysiol.2005.092031","article-title":"Mitofusins 1\/2 and ERRalpha expression are increased in human skeletal muscle after physical exercise","volume":"567","author":"Cartoni","year":"2005","journal-title":"J. Physiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1083\/jcb.200211046","article-title":"Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development","volume":"160","author":"Chen","year":"2003","journal-title":"J. Cell Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"4232","DOI":"10.1523\/JNEUROSCI.6248-09.2010","article-title":"Mitofusin 2 is necessary for transport of axonal mitochondria and interacts with the Miro\/Milton complex","volume":"30","author":"Misko","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1007\/s00109-010-0670-x","article-title":"The role of mitochondria in pulmonary vascular remodeling","volume":"88","author":"Dromparis","year":"2010","journal-title":"J. Mol. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1016\/j.yjmcc.2009.02.020","article-title":"Peroxisome proliferator-activated receptor delta regulates mitofusin 2 expression in the heart","volume":"46","author":"Li","year":"2009","journal-title":"J. Mol. Cell Cardiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1016\/S1471-4914(03)00046-7","article-title":"Mitochondria in cell death: Novel targets for neuroprotection and cardioprotection","volume":"9","author":"Mattson","year":"2003","journal-title":"Trends Mol. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1016\/j.mvr.2012.06.010","article-title":"Effect of Mitofusin 2 on smooth muscle cells proliferation in hypoxic pulmonary hypertension","volume":"84","author":"Zhang","year":"2012","journal-title":"Microvasc. Res."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Chen, L., Liu, B., Qin, Y., Li, A., Gao, M., Liu, H., and Gong, G. (2021). Mitochondrial Fusion Protein Mfn2 and Its Role in Heart Failure. Front. Mol. Biosci., 8.","DOI":"10.3389\/fmolb.2021.681237"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Nolfi-Donegan, D., Braganza, A., and Shiva, S. (2020). Mitochondrial electron transport chain: Oxidative phosphorylation, oxidant production, and methods of measurement. Redox Biol., 37.","DOI":"10.1016\/j.redox.2020.101674"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1042\/BJ20141171","article-title":"Mitochondrial pyruvate transport: A historical perspective and future research directions","volume":"466","author":"McCommis","year":"2015","journal-title":"Biochem. J."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1038\/s41392-020-00311-7","article-title":"NAD+ metabolism: Pathophysiologic mechanisms and therapeutic potential","volume":"5","author":"Xie","year":"2020","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_37","first-page":"357","article-title":"Endothelial cell energy metabolism, proliferation, and apoptosis in pulmonary hypertension","volume":"1","author":"Xu","year":"2011","journal-title":"Compr. Physiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1342","DOI":"10.1073\/pnas.0605080104","article-title":"Alterations of cellular bioenergetics in pulmonary artery endothelial cells","volume":"104","author":"Xu","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1038\/s41598-019-57200-5","article-title":"Stable isotope metabolomics of pulmonary artery smooth muscle and endothelial cells in pulmonary hypertension and with TGF-beta treatment","volume":"10","author":"Sanders","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Zhao, Y., Peng, J., Lu, C., Hsin, M., Mura, M., Wu, L., Chu, L., Zamel, R., Machuca, T., and Waddell, T. (2014). Metabolomic heterogeneity of pulmonary arterial hypertension. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0088727"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"18623","DOI":"10.1038\/s41598-019-55053-6","article-title":"Integrative proteomics and phosphoproteomics in pulmonary arterial hypertension","volume":"9","author":"Xu","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2484","DOI":"10.1111\/jcmm.14937","article-title":"Metabolomics reveals metabolite changes of patients with pulmonary arterial hypertension in China","volume":"24","author":"Chen","year":"2020","journal-title":"J. Cell Mol. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"H570","DOI":"10.1152\/ajpheart.01324.2007","article-title":"Mitochondrial metabolism, redox signaling, and fusion: A mitochondria-ROS-HIF-1\u03b1-Kv1.5 O2-sensing pathway at the intersection of pulmonary hypertension and cancer","volume":"294","author":"Archer","year":"2008","journal-title":"Am. J. Physiol.-Heart Circ. Physiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"L811","DOI":"10.1152\/ajplung.00302.2016","article-title":"Update on novel targets and potential treatment avenues in pulmonary hypertension","volume":"311","author":"Huetsch","year":"2016","journal-title":"Am. J. Physiol.-Lung Cell. Mol. Physiol."},{"key":"ref_45","first-page":"223","article-title":"STAT3 signaling in pulmonary arterial hypertension","volume":"1","author":"Paulin","year":"2012","journal-title":"Jakstat"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"L229","DOI":"10.1152\/ajplung.00238.2014","article-title":"The role of inflammation in hypoxic pulmonary hypertension: From cellular mechanisms to clinical phenotypes","volume":"308","author":"Pugliese","year":"2015","journal-title":"Am. J. Physiol.-Lung Cell. Mol. Physiol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"L962","DOI":"10.1152\/ajplung.00073.2014","article-title":"Mitochondria in lung biology and pathology: More than just a powerhouse","volume":"306","author":"Schumacker","year":"2014","journal-title":"Am. J. Physiol.-Lung Cell. Mol. Physiol."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Ryanto, G.R.T., Suraya, R., and Nagano, T. (2023). Mitochondrial Dysfunction in Pulmonary Hypertension. Antioxidants, 12.","DOI":"10.3390\/antiox12020372"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Lu, Q., Sun, X., Yegambaram, M., Ornatowski, W., Wu, X., Wang, H., Garcia-Flores, A., Da Silva, V., Zemskov, E.A., and Tang, H. (2023). Nitration-mediated activation of the small GTPase RhoA stimulates cellular glycolysis through enhanced mitochondrial fission. J. Biol. Chem., 299.","DOI":"10.1016\/j.jbc.2023.103067"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1164\/rccm.201209-1687OC","article-title":"PGC1\u03b1-mediated mitofusin-2 deficiency in female rats and humans with pulmonary arterial hypertension","volume":"187","author":"Ryan","year":"2013","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3301","DOI":"10.12659\/MSM.900487","article-title":"Upregulated miR-17 Regulates Hypoxia-Mediated Human Pulmonary Artery Smooth Muscle Cell Proliferation and Apoptosis by Targeting Mitofusin 2","volume":"22","author":"Lu","year":"2016","journal-title":"Med. Sci. Monit."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"14.10.1","DOI":"10.1002\/0471250953.bi1410s34","article-title":"Metabolomic Data Processing, Analysis, and Interpretation Using MetaboAnalyst","volume":"34","author":"Xia","year":"2011","journal-title":"Curr. Protoc. Bioinform."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.1165\/rcmb.2013-0187OC","article-title":"Endothelin-1 induces a glycolytic switch in pulmonary arterial endothelial cells via the mitochondrial translocation of endothelial nitric oxide synthase","volume":"50","author":"Sun","year":"2014","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1161\/01.CIR.0000102381.57477.50","article-title":"Endothelial Dysfunction in Pulmonary Hypertension","volume":"109","author":"Budhiraja","year":"2004","journal-title":"Circulation"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2045893217752912","DOI":"10.1177\/2045893217752912","article-title":"Endothelial dysfunction in pulmonary arterial hypertension: An evolving landscape (2017 Grover Conference Series)","volume":"8","author":"Ranchoux","year":"2018","journal-title":"Pulm. Circ."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1007\/s00109-015-1263-5","article-title":"Mitochondrial dynamics in pulmonary arterial hypertension","volume":"93","author":"Ryan","year":"2015","journal-title":"J. Mol. Med."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1484","DOI":"10.1161\/CIRCRESAHA.111.263848","article-title":"Dynamin-Related Protein 1 Mediated Mitochondrial Mitotic Fission Permits Hyperproliferation of Vascular Smooth Muscle Cells and Offers a Novel Therapeutic Target in Pulmonary Hypertension","volume":"110","author":"Marsboom","year":"2012","journal-title":"Circ. Res."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Luo, F., Fu, M., Wang, T., Qi, Y., Zhong, X., Li, D., and Liu, B. (2023). Down-regulation of the mitochondrial fusion protein Opa1\/Mfn2 promotes cardiomyocyte hypertrophy in Su5416\/hypoxia-induced pulmonary hypertension rats. Arch. Biochem. Biophys., 747.","DOI":"10.1016\/j.abb.2023.109743"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"411","DOI":"10.3389\/fphys.2019.00411","article-title":"Mitofusin 2 Participates in Mitophagy and Mitochondrial Fusion Against Angiotensin II-Induced Cardiomyocyte Injury","volume":"10","author":"Xiong","year":"2019","journal-title":"Front. Physiol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1677","DOI":"10.15252\/embj.201593084","article-title":"Mfn2 deficiency links age-related sarcopenia and impaired autophagy to activation of an adaptive mitophagy pathway","volume":"35","author":"Sorianello","year":"2016","journal-title":"EMBO J."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1016\/j.yjmcc.2011.07.023","article-title":"Mitofusins are required for angiogenic function and modulate different signaling pathways in cultured endothelial cells","volume":"51","author":"Lugus","year":"2011","journal-title":"J. Mol. Cell Cardiol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"2486","DOI":"10.1161\/CIRCULATIONAHA.117.031655","article-title":"Pyruvate Kinase and Warburg Metabolism in Pulmonary Arterial Hypertension: Uncoupled Glycolysis and the Cancer-Like Phenotype of Pulmonary Arterial Hypertension","volume":"136","author":"Archer","year":"2017","journal-title":"Circulation"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1164\/rccm.200709-1369PP","article-title":"The cancer paradigm of severe pulmonary arterial hypertension","volume":"178","author":"Rai","year":"2008","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"L46","DOI":"10.1152\/ajplung.00247.2007","article-title":"Altered carnitine homeostasis is associated with decreased mitochondrial function and altered nitric oxide signaling in lambs with pulmonary hypertension","volume":"294","author":"Sharma","year":"2008","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1038\/pr.2013.71","article-title":"L-carnitine preserves endothelial function in a lamb model of increased pulmonary blood flow","volume":"74","author":"Sharma","year":"2013","journal-title":"Pediatr. Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1038\/s41467-019-13668-3","article-title":"Mitochondrial TCA cycle metabolites control physiology and disease","volume":"11","author":"Chandel","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"e14018","DOI":"10.1111\/apha.14018","article-title":"MFN2 deficiency promotes cardiac response to hypobaric hypoxia by reprogramming cardiomyocyte metabolism","volume":"239","author":"Zhang","year":"2023","journal-title":"Acta Physiol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1161\/CIRCRESAHA.115.301130","article-title":"The metabolic theory of pulmonary arterial hypertension","volume":"115","author":"Paulin","year":"2014","journal-title":"Circ. Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"e21426","DOI":"10.1096\/fj.202002464R","article-title":"Reduced electron transport chain complex I protein abundance and function in Mfn2-deficient myogenic progenitors lead to oxidative stress and mitochondria swelling","volume":"35","author":"Luo","year":"2021","journal-title":"FASEB J."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/nrc3183","article-title":"HIF1alpha and HIF2alpha: Sibling rivalry in hypoxic tumour growth and progression","volume":"12","author":"Keith","year":"2011","journal-title":"Nat. Rev. Cancer"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"3664","DOI":"10.1172\/JCI67230","article-title":"HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations","volume":"123","author":"Semenza","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1130","DOI":"10.2353\/ajpath.2010.090832","article-title":"Hypoxia inducible-factor1alpha regulates the metabolic shift of pulmonary hypertensive endothelial cells","volume":"176","author":"Fijalkowska","year":"2010","journal-title":"Am. J. Pathol."},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Huang, X., Zhao, L., and Peng, R. (2023). Hypoxia-Inducible Factor 1 and Mitochondria: An Intimate Connection. Biomolecules, 13.","DOI":"10.3390\/biom13010050"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"25130","DOI":"10.1074\/jbc.M001914200","article-title":"Reactive Oxygen Species Generated at Mitochondrial Complex III Stabilize Hypoxia-inducible Factor-1\u03b1 during Hypoxia: A MECHANISM OF O2 SENSING *","volume":"275","author":"Chandel","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.1164\/ajrccm.164.6.2104033","article-title":"Increased lipid peroxidation in patients with pulmonary hypertension","volume":"164","author":"Cracowski","year":"2001","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1023\/A:1020238026534","article-title":"Oxidative stress in patients with primary pulmonary hypertension","volume":"133","author":"Irodova","year":"2002","journal-title":"Bull. Exp. Biol. Med."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1164\/rccm.200301-147OC","article-title":"Oxidative stress in severe pulmonary hypertension","volume":"169","author":"Bowers","year":"2004","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"5583","DOI":"10.1038\/s41598-021-85004-z","article-title":"Protein network analyses of pulmonary endothelial cells in chronic thromboembolic pulmonary hypertension","volume":"11","author":"Nukala","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.yjmcc.2016.01.009","article-title":"Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to the development of pulmonary arterial hypertension","volume":"91","author":"Guo","year":"2016","journal-title":"J. Mol. Cell Cardiol."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Yu, T., Wang, L., Zhang, L., and Deuster, P.A. (2023). Mitochondrial Fission as a Therapeutic Target for Metabolic Diseases: Insights into Antioxidant Strategies. Antioxidants, 12.","DOI":"10.3390\/antiox12061163"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"108079","DOI":"10.1016\/j.celrep.2020.108079","article-title":"Mitofusin 2 in Macrophages Links Mitochondrial ROS Production, Cytokine Release, Phagocytosis, Autophagy, and Bactericidal Activity","volume":"32","author":"Tur","year":"2020","journal-title":"Cell Rep."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"e61119","DOI":"10.7554\/eLife.61119","article-title":"Burst mitofusin activation reverses neuromuscular dysfunction in murine CMT2A","volume":"9","author":"Franco","year":"2020","journal-title":"Elife"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"L650","DOI":"10.1152\/ajplung.00252.2002","article-title":"Developmental differences in the shear stress-induced expression of endothelial NO synthase: Changing role of AP-1","volume":"284","author":"Wedgwood","year":"2003","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"L984","DOI":"10.1152\/ajplung.00224.2003","article-title":"Nitric oxide decreases endothelin-1 secretion through the activation of soluble guanylate cyclase","volume":"286","author":"Kelly","year":"2004","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"110849","DOI":"10.1016\/j.ecoenv.2020.110849","article-title":"2,2\u2032,4,4\u2032-tetrabromodiphenyl ether (BDE-47) induces wide metabolic changes including attenuated mitochondrial function and enhanced glycolysis in PC12 cells","volume":"201","author":"He","year":"2020","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"11728","DOI":"10.1021\/acs.analchem.0c01767","article-title":"Comprehensive Isotopic Targeted Mass Spectrometry: Reliable Metabolic Flux Analysis with Broad Coverage","volume":"92","author":"Shi","year":"2020","journal-title":"Anal. Chem."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"2791","DOI":"10.1021\/acs.jproteome.9b00100","article-title":"Coccidioidomycosis Detection Using Targeted Plasma and Urine Metabolic Profiling","volume":"18","author":"Jasbi","year":"2019","journal-title":"J. Proteome Res."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1735","DOI":"10.1038\/s41596-022-00710-w","article-title":"Using MetaboAnalyst 5.0 for LC\u2013HRMS spectra processing, multi-omics integration and covariate adjustment of global metabolomics data","volume":"17","author":"Pang","year":"2022","journal-title":"Nat. Protoc."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1126\/science.aao1785","article-title":"MFN2 agonists reverse mitochondrial defects in preclinical models of Charcot-Marie-Tooth disease type 2A","volume":"360","author":"Rocha","year":"2018","journal-title":"Science"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1294","DOI":"10.1093\/bioinformatics\/bts127","article-title":"IsoCor: Correcting MS data in isotope labeling experiments","volume":"28","author":"Millard","year":"2012","journal-title":"Bioinformatics"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/24\/17533\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:39:43Z","timestamp":1760132383000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/24\/17533"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,15]]},"references-count":90,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["ijms242417533"],"URL":"https:\/\/doi.org\/10.3390\/ijms242417533","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,15]]}}}