Altered Expression Ratio of Actin-Binding Gelsolin Isoforms Is a Novel Hallmark of Mitochondrial OXPHOS Dysfunction
Mitochondrial oxidative phosphorylation (OXPHOS) defects are the primary cause of inborn errors of energy metabolism. Despite considerable progress on their genetic basis, their global pathophysiological consequences remain undefined. Previous studies reported that OXPHOS dysfunction associated with...
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MDPI AG
2020-08-01
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| Online Access: | https://www.mdpi.com/2073-4409/9/9/1922 |
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| author | Alberto García-Bartolomé Ana Peñas María Illescas Verónica Bermejo Sandra López-Calcerrada Rafael Pérez-Pérez Lorena Marín-Buera Cristina Domínguez-González Joaquín Arenas Miguel A. Martín Cristina Ugalde |
| author_facet | Alberto García-Bartolomé Ana Peñas María Illescas Verónica Bermejo Sandra López-Calcerrada Rafael Pérez-Pérez Lorena Marín-Buera Cristina Domínguez-González Joaquín Arenas Miguel A. Martín Cristina Ugalde |
| author_sort | Alberto García-Bartolomé |
| collection | DOAJ |
| description | Mitochondrial oxidative phosphorylation (OXPHOS) defects are the primary cause of inborn errors of energy metabolism. Despite considerable progress on their genetic basis, their global pathophysiological consequences remain undefined. Previous studies reported that OXPHOS dysfunction associated with complex III deficiency exacerbated the expression and mitochondrial location of cytoskeletal gelsolin (GSN) to promote cell survival responses. In humans, besides the cytosolic isoform, GSN presents a plasma isoform secreted to extracellular environments. We analyzed the interplay between both GSN isoforms in human cellular and clinical models of OXPHOS dysfunction. Regardless of its pathogenic origin, OXPHOS dysfunction induced the physiological upregulation of cytosolic GSN in the mitochondria (mGSN), in parallel with a significant downregulation of plasma GSN (pGSN) levels. Consequently, significantly high mGSN-to-pGSN ratios were associated with OXPHOS deficiency both in human cells and blood. In contrast, control cells subjected to hydrogen peroxide or staurosporine treatments showed no correlation between oxidative stress or cell death induction and the altered levels and subcellular location of GSN isoforms, suggesting their specificity for OXPHOS dysfunction. In conclusion, a high mitochondrial-to-plasma GSN ratio represents a useful cellular indicator of OXPHOS defects, with potential use for future research of a wide range of clinical conditions with mitochondrial involvement. |
| first_indexed | 2024-03-10T17:12:59Z |
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| id | doaj.art-3625133fae8046d0a3d4acb71b41e3ba |
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| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T17:12:59Z |
| publishDate | 2020-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-3625133fae8046d0a3d4acb71b41e3ba2023-11-20T10:35:50ZengMDPI AGCells2073-44092020-08-0199192210.3390/cells9091922Altered Expression Ratio of Actin-Binding Gelsolin Isoforms Is a Novel Hallmark of Mitochondrial OXPHOS DysfunctionAlberto García-Bartolomé0Ana Peñas1María Illescas2Verónica Bermejo3Sandra López-Calcerrada4Rafael Pérez-Pérez5Lorena Marín-Buera6Cristina Domínguez-González7Joaquín Arenas8Miguel A. Martín9Cristina Ugalde10Laboratorio de Enfermedades Mitocondriales y Neurometabólicas, Instituto de Investigación Hospital 12 de Octubre (i+12), 28041 Madrid, SpainLaboratorio de Enfermedades Mitocondriales y Neurometabólicas, Instituto de Investigación Hospital 12 de Octubre (i+12), 28041 Madrid, SpainLaboratorio de Enfermedades Mitocondriales y Neurometabólicas, Instituto de Investigación Hospital 12 de Octubre (i+12), 28041 Madrid, SpainLaboratorio de Enfermedades Mitocondriales y Neurometabólicas, Instituto de Investigación Hospital 12 de Octubre (i+12), 28041 Madrid, SpainLaboratorio de Enfermedades Mitocondriales y Neurometabólicas, Instituto de Investigación Hospital 12 de Octubre (i+12), 28041 Madrid, SpainLaboratorio de Enfermedades Mitocondriales y Neurometabólicas, Instituto de Investigación Hospital 12 de Octubre (i+12), 28041 Madrid, SpainLaboratorio de Enfermedades Mitocondriales y Neurometabólicas, Instituto de Investigación Hospital 12 de Octubre (i+12), 28041 Madrid, SpainLaboratorio de Enfermedades Mitocondriales y Neurometabólicas, Instituto de Investigación Hospital 12 de Octubre (i+12), 28041 Madrid, SpainLaboratorio de Enfermedades Mitocondriales y Neurometabólicas, Instituto de Investigación Hospital 12 de Octubre (i+12), 28041 Madrid, SpainLaboratorio de Enfermedades Mitocondriales y Neurometabólicas, Instituto de Investigación Hospital 12 de Octubre (i+12), 28041 Madrid, SpainLaboratorio de Enfermedades Mitocondriales y Neurometabólicas, Instituto de Investigación Hospital 12 de Octubre (i+12), 28041 Madrid, SpainMitochondrial oxidative phosphorylation (OXPHOS) defects are the primary cause of inborn errors of energy metabolism. Despite considerable progress on their genetic basis, their global pathophysiological consequences remain undefined. Previous studies reported that OXPHOS dysfunction associated with complex III deficiency exacerbated the expression and mitochondrial location of cytoskeletal gelsolin (GSN) to promote cell survival responses. In humans, besides the cytosolic isoform, GSN presents a plasma isoform secreted to extracellular environments. We analyzed the interplay between both GSN isoforms in human cellular and clinical models of OXPHOS dysfunction. Regardless of its pathogenic origin, OXPHOS dysfunction induced the physiological upregulation of cytosolic GSN in the mitochondria (mGSN), in parallel with a significant downregulation of plasma GSN (pGSN) levels. Consequently, significantly high mGSN-to-pGSN ratios were associated with OXPHOS deficiency both in human cells and blood. In contrast, control cells subjected to hydrogen peroxide or staurosporine treatments showed no correlation between oxidative stress or cell death induction and the altered levels and subcellular location of GSN isoforms, suggesting their specificity for OXPHOS dysfunction. In conclusion, a high mitochondrial-to-plasma GSN ratio represents a useful cellular indicator of OXPHOS defects, with potential use for future research of a wide range of clinical conditions with mitochondrial involvement.https://www.mdpi.com/2073-4409/9/9/1922mitochondriaOXPHOS dysfunctionoxidative stressactin cytoskeletongelsolin isoformsGSN |
| spellingShingle | Alberto García-Bartolomé Ana Peñas María Illescas Verónica Bermejo Sandra López-Calcerrada Rafael Pérez-Pérez Lorena Marín-Buera Cristina Domínguez-González Joaquín Arenas Miguel A. Martín Cristina Ugalde Altered Expression Ratio of Actin-Binding Gelsolin Isoforms Is a Novel Hallmark of Mitochondrial OXPHOS Dysfunction Cells mitochondria OXPHOS dysfunction oxidative stress actin cytoskeleton gelsolin isoforms GSN |
| title | Altered Expression Ratio of Actin-Binding Gelsolin Isoforms Is a Novel Hallmark of Mitochondrial OXPHOS Dysfunction |
| title_full | Altered Expression Ratio of Actin-Binding Gelsolin Isoforms Is a Novel Hallmark of Mitochondrial OXPHOS Dysfunction |
| title_fullStr | Altered Expression Ratio of Actin-Binding Gelsolin Isoforms Is a Novel Hallmark of Mitochondrial OXPHOS Dysfunction |
| title_full_unstemmed | Altered Expression Ratio of Actin-Binding Gelsolin Isoforms Is a Novel Hallmark of Mitochondrial OXPHOS Dysfunction |
| title_short | Altered Expression Ratio of Actin-Binding Gelsolin Isoforms Is a Novel Hallmark of Mitochondrial OXPHOS Dysfunction |
| title_sort | altered expression ratio of actin binding gelsolin isoforms is a novel hallmark of mitochondrial oxphos dysfunction |
| topic | mitochondria OXPHOS dysfunction oxidative stress actin cytoskeleton gelsolin isoforms GSN |
| url | https://www.mdpi.com/2073-4409/9/9/1922 |
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