Similar deficiencies, different outcomes: succinate dehydrogenase loss in adrenal medulla vs. fibroblast cell culture models of paraganglioma
Abstract Heterozygosity for loss-of‐function alleles of the genes encoding the four subunits of succinate dehydrogenase (SDHA, SDHB, SDHC, SDHD), as well as the SDHAF2 assembly factor predispose affected individuals to pheochromocytoma and paraganglioma (PPGL), two rare neuroendocrine tumors that ar...
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BMC
2024-12-01
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| Series: | Cancer & Metabolism |
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| Online Access: | https://doi.org/10.1186/s40170-024-00369-9 |
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| author | Fatimah J. Al Khazal Sanjana Mahadev Bhat Yuxiang Zhu Cristina M. de Araujo Correia Sherry X. Zhou Brandon A. Wilbanks Clifford D. Folmes Gary C. Sieck Judith Favier L. James Maher |
| author_facet | Fatimah J. Al Khazal Sanjana Mahadev Bhat Yuxiang Zhu Cristina M. de Araujo Correia Sherry X. Zhou Brandon A. Wilbanks Clifford D. Folmes Gary C. Sieck Judith Favier L. James Maher |
| author_sort | Fatimah J. Al Khazal |
| collection | DOAJ |
| description | Abstract Heterozygosity for loss-of‐function alleles of the genes encoding the four subunits of succinate dehydrogenase (SDHA, SDHB, SDHC, SDHD), as well as the SDHAF2 assembly factor predispose affected individuals to pheochromocytoma and paraganglioma (PPGL), two rare neuroendocrine tumors that arise from neural crest-derived paraganglia. Tumorigenesis results from loss of the remaining functional SDHx gene copy, leading to a cell with no functional SDH and a defective tricarboxylic acid (TCA) cycle. It is believed that the subsequent accumulation of succinate competitively inhibits multiple dioxygenase enzymes that normally suppress hypoxic signaling and demethylate histones and DNA, ultimately leading to increased expression of genes involved in angiogenesis and cell proliferation. Why SDH loss is selectively tumorigenic in neuroendocrine cells remains poorly understood. In the absence of SDH-loss tumor-derived cell models, the cellular burden of SDH loss and succinate accumulation have been investigated through conditional knockouts of SDH subunits in pre-existing murine or human cell lines with varying degrees of clinical relevance. Here we characterize two available murine SDH-loss cell lines, immortalized adrenally-derived premature chromaffin cells vs. immortalized fibroblasts, at a level of detail beyond that currently reported in the literature and with the intention of laying the foundation for future investigations into adaptive pathways and vulnerabilities in SDH-loss cells. We report different mechanistic and phenotypic manifestations of SDH subunit loss in the presented cellular contexts. These findings highlight similarities and differences in the cellular response to SDH loss between the two cell models. We show that adrenally-derived cells display more severe morphological cellular and mitochondrial alterations, yet are unique in preserving residual Complex I function, perhaps allowing them to better tolerate SDH loss, thus making them a closer model to SDH-loss PPGL relative to fibroblasts. (281 words) |
| format | Article |
| id | doaj-art-e02144bff4c84b45bd8b7b9e41a749d2 |
| institution | Kabale University |
| issn | 2049-3002 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Cancer & Metabolism |
| spelling | doaj-art-e02144bff4c84b45bd8b7b9e41a749d22024-12-29T12:42:12ZengBMCCancer & Metabolism2049-30022024-12-0112111710.1186/s40170-024-00369-9Similar deficiencies, different outcomes: succinate dehydrogenase loss in adrenal medulla vs. fibroblast cell culture models of paragangliomaFatimah J. Al Khazal0Sanjana Mahadev Bhat1Yuxiang Zhu2Cristina M. de Araujo Correia3Sherry X. Zhou4Brandon A. Wilbanks5Clifford D. Folmes6Gary C. Sieck7Judith Favier8L. James Maher9Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic College of Medicine and ScienceDepartment of Physiology and Biomedical Engineering, Mayo ClinicDepartment of Biochemistry and Molecular Biology, Mayo ClinicDepartment of Molecular Pharmacology and Experimental Therapeutics, Mayo ClinicMayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic College of Medicine and ScienceMayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic College of Medicine and ScienceDepartment of Biochemistry and Molecular Biology, Mayo ClinicDepartment of Physiology and Biomedical Engineering, Mayo ClinicInserm, Centre de recherche des Cordeliers, Université Paris-Cité, Sorbonne Université, Equipe Labellisée Ligue contre le CancerDepartment of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and ScienceAbstract Heterozygosity for loss-of‐function alleles of the genes encoding the four subunits of succinate dehydrogenase (SDHA, SDHB, SDHC, SDHD), as well as the SDHAF2 assembly factor predispose affected individuals to pheochromocytoma and paraganglioma (PPGL), two rare neuroendocrine tumors that arise from neural crest-derived paraganglia. Tumorigenesis results from loss of the remaining functional SDHx gene copy, leading to a cell with no functional SDH and a defective tricarboxylic acid (TCA) cycle. It is believed that the subsequent accumulation of succinate competitively inhibits multiple dioxygenase enzymes that normally suppress hypoxic signaling and demethylate histones and DNA, ultimately leading to increased expression of genes involved in angiogenesis and cell proliferation. Why SDH loss is selectively tumorigenic in neuroendocrine cells remains poorly understood. In the absence of SDH-loss tumor-derived cell models, the cellular burden of SDH loss and succinate accumulation have been investigated through conditional knockouts of SDH subunits in pre-existing murine or human cell lines with varying degrees of clinical relevance. Here we characterize two available murine SDH-loss cell lines, immortalized adrenally-derived premature chromaffin cells vs. immortalized fibroblasts, at a level of detail beyond that currently reported in the literature and with the intention of laying the foundation for future investigations into adaptive pathways and vulnerabilities in SDH-loss cells. We report different mechanistic and phenotypic manifestations of SDH subunit loss in the presented cellular contexts. These findings highlight similarities and differences in the cellular response to SDH loss between the two cell models. We show that adrenally-derived cells display more severe morphological cellular and mitochondrial alterations, yet are unique in preserving residual Complex I function, perhaps allowing them to better tolerate SDH loss, thus making them a closer model to SDH-loss PPGL relative to fibroblasts. (281 words)https://doi.org/10.1186/s40170-024-00369-9Succinate dehydrogenasePheochromocytomaParagangliomaTricarboxylic acid cycleHypoxiaComplex I |
| spellingShingle | Fatimah J. Al Khazal Sanjana Mahadev Bhat Yuxiang Zhu Cristina M. de Araujo Correia Sherry X. Zhou Brandon A. Wilbanks Clifford D. Folmes Gary C. Sieck Judith Favier L. James Maher Similar deficiencies, different outcomes: succinate dehydrogenase loss in adrenal medulla vs. fibroblast cell culture models of paraganglioma Cancer & Metabolism Succinate dehydrogenase Pheochromocytoma Paraganglioma Tricarboxylic acid cycle Hypoxia Complex I |
| title | Similar deficiencies, different outcomes: succinate dehydrogenase loss in adrenal medulla vs. fibroblast cell culture models of paraganglioma |
| title_full | Similar deficiencies, different outcomes: succinate dehydrogenase loss in adrenal medulla vs. fibroblast cell culture models of paraganglioma |
| title_fullStr | Similar deficiencies, different outcomes: succinate dehydrogenase loss in adrenal medulla vs. fibroblast cell culture models of paraganglioma |
| title_full_unstemmed | Similar deficiencies, different outcomes: succinate dehydrogenase loss in adrenal medulla vs. fibroblast cell culture models of paraganglioma |
| title_short | Similar deficiencies, different outcomes: succinate dehydrogenase loss in adrenal medulla vs. fibroblast cell culture models of paraganglioma |
| title_sort | similar deficiencies different outcomes succinate dehydrogenase loss in adrenal medulla vs fibroblast cell culture models of paraganglioma |
| topic | Succinate dehydrogenase Pheochromocytoma Paraganglioma Tricarboxylic acid cycle Hypoxia Complex I |
| url | https://doi.org/10.1186/s40170-024-00369-9 |
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