Rescue of Mitochondrial Function in Hutchinson-Gilford Progeria Syndrome by the Pharmacological Modulation of Exportin CRM1
Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disorder caused by the expression of progerin, a mutant variant of Lamin A. Recently, HGPS studies have gained relevance because unraveling its underlying mechanism would help to understand physiological aging. We previously repor...
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MDPI AG
2023-01-01
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| author | Feliciano Monterrubio-Ledezma Fernando Navarro-García Lourdes Massieu Ricardo Mondragón-Flores Luz Adriana Soto-Ponce Jonathan J. Magaña Bulmaro Cisneros |
| author_facet | Feliciano Monterrubio-Ledezma Fernando Navarro-García Lourdes Massieu Ricardo Mondragón-Flores Luz Adriana Soto-Ponce Jonathan J. Magaña Bulmaro Cisneros |
| author_sort | Feliciano Monterrubio-Ledezma |
| collection | DOAJ |
| description | Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disorder caused by the expression of progerin, a mutant variant of Lamin A. Recently, HGPS studies have gained relevance because unraveling its underlying mechanism would help to understand physiological aging. We previously reported that the CRM1-mediated nuclear protein export pathway is exacerbated in HGPS cells, provoking the mislocalization of numerous protein targets of CRM1. We showed that normalization of this mechanism by pharmacologically inhibiting CRM1 with LMB (specific CRM1 inhibitor), mitigates the senescent phenotype of HGPS cells. Since mitochondrial dysfunction is a hallmark of HGPS, in this study we analyze the effect of LMB on mitochondrial function. Remarkably, LMB treatment induced the recovery of mitochondrial function in HGPS cells, as shown by the improvement in mitochondrial morphology, mitochondrial membrane potential, and ATP levels, which consequently impeded the accumulation of ROS but not mitochondrial superoxide. We provide evidence that the beneficial effect of LMB is mechanistically based on a combinatory effect on mitochondrial biogenesis via upregulation of PGC-1α expression (master transcription cofactor of mitochondrial genes), and mitophagy through the recovery of lysosomal content. The use of exportin CRM1 inhibitors constitutes a promising strategy to treat HGPS and other diseases characterized by mitochondrial impairment. |
| first_indexed | 2024-03-09T13:12:30Z |
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| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-09T13:12:30Z |
| publishDate | 2023-01-01 |
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| record_format | Article |
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| spelling | doaj.art-522ab2153bd04ec2928cf2b54562f7442023-11-30T21:40:10ZengMDPI AGCells2073-44092023-01-0112227510.3390/cells12020275Rescue of Mitochondrial Function in Hutchinson-Gilford Progeria Syndrome by the Pharmacological Modulation of Exportin CRM1Feliciano Monterrubio-Ledezma0Fernando Navarro-García1Lourdes Massieu2Ricardo Mondragón-Flores3Luz Adriana Soto-Ponce4Jonathan J. Magaña5Bulmaro Cisneros6Department of Genetics and Molecular Biology, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV), Mexico City 07360, MexicoDepartment of Cell Biology, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV), Mexico City 07360, MexicoDepartment of Neuropathology, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Mexico City 04510, MexicoDepartment of Biochemistry, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV), Mexico City 07360, MexicoDepartment of Genetics and Molecular Biology, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV), Mexico City 07360, MexicoDepartament of Bioengineering, Escuela de Ingeniería y Ciencias, Tecnológico de Monterrey-Campus Ciudad de México, Ciudad de Mexico 14380, MexicoDepartment of Genetics and Molecular Biology, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV), Mexico City 07360, MexicoHutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disorder caused by the expression of progerin, a mutant variant of Lamin A. Recently, HGPS studies have gained relevance because unraveling its underlying mechanism would help to understand physiological aging. We previously reported that the CRM1-mediated nuclear protein export pathway is exacerbated in HGPS cells, provoking the mislocalization of numerous protein targets of CRM1. We showed that normalization of this mechanism by pharmacologically inhibiting CRM1 with LMB (specific CRM1 inhibitor), mitigates the senescent phenotype of HGPS cells. Since mitochondrial dysfunction is a hallmark of HGPS, in this study we analyze the effect of LMB on mitochondrial function. Remarkably, LMB treatment induced the recovery of mitochondrial function in HGPS cells, as shown by the improvement in mitochondrial morphology, mitochondrial membrane potential, and ATP levels, which consequently impeded the accumulation of ROS but not mitochondrial superoxide. We provide evidence that the beneficial effect of LMB is mechanistically based on a combinatory effect on mitochondrial biogenesis via upregulation of PGC-1α expression (master transcription cofactor of mitochondrial genes), and mitophagy through the recovery of lysosomal content. The use of exportin CRM1 inhibitors constitutes a promising strategy to treat HGPS and other diseases characterized by mitochondrial impairment.https://www.mdpi.com/2073-4409/12/2/275Hutchinson-Gilford progeria syndromemitochondriaCRM1leptomycin BmitophagyPGC-1α |
| spellingShingle | Feliciano Monterrubio-Ledezma Fernando Navarro-García Lourdes Massieu Ricardo Mondragón-Flores Luz Adriana Soto-Ponce Jonathan J. Magaña Bulmaro Cisneros Rescue of Mitochondrial Function in Hutchinson-Gilford Progeria Syndrome by the Pharmacological Modulation of Exportin CRM1 Cells Hutchinson-Gilford progeria syndrome mitochondria CRM1 leptomycin B mitophagy PGC-1α |
| title | Rescue of Mitochondrial Function in Hutchinson-Gilford Progeria Syndrome by the Pharmacological Modulation of Exportin CRM1 |
| title_full | Rescue of Mitochondrial Function in Hutchinson-Gilford Progeria Syndrome by the Pharmacological Modulation of Exportin CRM1 |
| title_fullStr | Rescue of Mitochondrial Function in Hutchinson-Gilford Progeria Syndrome by the Pharmacological Modulation of Exportin CRM1 |
| title_full_unstemmed | Rescue of Mitochondrial Function in Hutchinson-Gilford Progeria Syndrome by the Pharmacological Modulation of Exportin CRM1 |
| title_short | Rescue of Mitochondrial Function in Hutchinson-Gilford Progeria Syndrome by the Pharmacological Modulation of Exportin CRM1 |
| title_sort | rescue of mitochondrial function in hutchinson gilford progeria syndrome by the pharmacological modulation of exportin crm1 |
| topic | Hutchinson-Gilford progeria syndrome mitochondria CRM1 leptomycin B mitophagy PGC-1α |
| url | https://www.mdpi.com/2073-4409/12/2/275 |
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