Mitochondrial fission produces a Warburg effect via the oxidative inhibition of prolyl hydroxylase domain-2
Excessive mitochondrial fission and a shift to a Warburg phenotype are hallmarks of pulmonary hypertension (PH), although the mechanistic link between these processes remains unclear. We show that in pulmonary arterial endothelial cells (PAEC), Drp1 overexpression induces mitochondrial fission and i...
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| Language: | English |
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Elsevier
2025-04-01
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| Series: | Redox Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231725000424 |
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| author | Xutong Sun Manivannan Yegambaram Qing Lu Alejandro E. Garcia Flores Marissa D. Pokharel Jamie Soto Saurabh Aggarwal Ting Wang Jeffrey R. Fineman Stephen M. Black |
| author_facet | Xutong Sun Manivannan Yegambaram Qing Lu Alejandro E. Garcia Flores Marissa D. Pokharel Jamie Soto Saurabh Aggarwal Ting Wang Jeffrey R. Fineman Stephen M. Black |
| author_sort | Xutong Sun |
| collection | DOAJ |
| description | Excessive mitochondrial fission and a shift to a Warburg phenotype are hallmarks of pulmonary hypertension (PH), although the mechanistic link between these processes remains unclear. We show that in pulmonary arterial endothelial cells (PAEC), Drp1 overexpression induces mitochondrial fission and increases glycolytic ATP production and glycolysis. This is due to mitochondrial reactive oxygen species (mito-ROS)-mediated activation of hypoxia-inducible factor-1α (HIF-1α) signaling, and this is linked to hydrogen peroxide (H2O2)-mediated inhibition of prolyl hydroxylase domain-2 (PHD2) due to its cysteine 326 oxidation and dimerization. Furthermore, these findings are validated in PAEC isolated from a lamb model of PH, which are glycolytic (Shunt PAEC), exhibit increases in both H2O2 and PHD2 dimer levels. The overexpression of catalase reversed the PHD2 dimerization, decreased HIF-1α levels, and attenuated glycolysis in Shunt PAEC. Our data suggest that reducing PHD2 dimerization could be a potential therapeutic target for PH. |
| format | Article |
| id | doaj-art-8f42a596f7874ab38d2b2b79836e37ae |
| institution | DOAJ |
| issn | 2213-2317 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj-art-8f42a596f7874ab38d2b2b79836e37ae2025-08-20T03:02:56ZengElsevierRedox Biology2213-23172025-04-018110352910.1016/j.redox.2025.103529Mitochondrial fission produces a Warburg effect via the oxidative inhibition of prolyl hydroxylase domain-2Xutong Sun0Manivannan Yegambaram1Qing Lu2Alejandro E. Garcia Flores3Marissa D. Pokharel4Jamie Soto5Saurabh Aggarwal6Ting Wang7Jeffrey R. Fineman8Stephen M. Black9Florida International University, Center for Translational Science, Port Saint Lucie, FL, 34987, USAFlorida International University, Center for Translational Science, Port Saint Lucie, FL, 34987, USAFlorida International University, Center for Translational Science, Port Saint Lucie, FL, 34987, USAFlorida International University, Center for Translational Science, Port Saint Lucie, FL, 34987, USAFlorida International University, Center for Translational Science, Port Saint Lucie, FL, 34987, USA; The Departments of Cellular & Molecular Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, 33199, USAFlorida International University, Center for Translational Science, Port Saint Lucie, FL, 34987, USAThe Departments of Cellular & Molecular Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, 33199, USAFlorida International University, Center for Translational Science, Port Saint Lucie, FL, 34987, USA; The Departments of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work, University of California San Francisco, San Francisco, CA, 94143, USAThe Department of Pediatrics, University of California San Francisco, San Francisco, CA, 94143, USA; The Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, 94143, USAFlorida International University, Center for Translational Science, Port Saint Lucie, FL, 34987, USA; The Departments of Cellular & Molecular Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, 33199, USA; The Departments of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work, University of California San Francisco, San Francisco, CA, 94143, USA; Corresponding author. FIU-Center for Translational Science, Florida International University, Port Saint Lucie, FL, 34987, USA.Excessive mitochondrial fission and a shift to a Warburg phenotype are hallmarks of pulmonary hypertension (PH), although the mechanistic link between these processes remains unclear. We show that in pulmonary arterial endothelial cells (PAEC), Drp1 overexpression induces mitochondrial fission and increases glycolytic ATP production and glycolysis. This is due to mitochondrial reactive oxygen species (mito-ROS)-mediated activation of hypoxia-inducible factor-1α (HIF-1α) signaling, and this is linked to hydrogen peroxide (H2O2)-mediated inhibition of prolyl hydroxylase domain-2 (PHD2) due to its cysteine 326 oxidation and dimerization. Furthermore, these findings are validated in PAEC isolated from a lamb model of PH, which are glycolytic (Shunt PAEC), exhibit increases in both H2O2 and PHD2 dimer levels. The overexpression of catalase reversed the PHD2 dimerization, decreased HIF-1α levels, and attenuated glycolysis in Shunt PAEC. Our data suggest that reducing PHD2 dimerization could be a potential therapeutic target for PH.http://www.sciencedirect.com/science/article/pii/S2213231725000424Mitochondrial fissionWarburg effectDrp1HIF-1 alphaPHD2Hydrogen peroxide |
| spellingShingle | Xutong Sun Manivannan Yegambaram Qing Lu Alejandro E. Garcia Flores Marissa D. Pokharel Jamie Soto Saurabh Aggarwal Ting Wang Jeffrey R. Fineman Stephen M. Black Mitochondrial fission produces a Warburg effect via the oxidative inhibition of prolyl hydroxylase domain-2 Redox Biology Mitochondrial fission Warburg effect Drp1 HIF-1 alpha PHD2 Hydrogen peroxide |
| title | Mitochondrial fission produces a Warburg effect via the oxidative inhibition of prolyl hydroxylase domain-2 |
| title_full | Mitochondrial fission produces a Warburg effect via the oxidative inhibition of prolyl hydroxylase domain-2 |
| title_fullStr | Mitochondrial fission produces a Warburg effect via the oxidative inhibition of prolyl hydroxylase domain-2 |
| title_full_unstemmed | Mitochondrial fission produces a Warburg effect via the oxidative inhibition of prolyl hydroxylase domain-2 |
| title_short | Mitochondrial fission produces a Warburg effect via the oxidative inhibition of prolyl hydroxylase domain-2 |
| title_sort | mitochondrial fission produces a warburg effect via the oxidative inhibition of prolyl hydroxylase domain 2 |
| topic | Mitochondrial fission Warburg effect Drp1 HIF-1 alpha PHD2 Hydrogen peroxide |
| url | http://www.sciencedirect.com/science/article/pii/S2213231725000424 |
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