Autophagy Inhibitors Do Not Restore Peroxisomal Functions in Cells With the Most Common Peroxisome Biogenesis Defect
Peroxisome biogenesis disorders within the Zellweger spectrum (PBD-ZSDs) are most frequently associated with the c.2528G>A (p.G843D) mutation in the PEX1 gene (PEX1-G843D), which results in impaired import of peroxisomal matrix proteins and, consequently, defective peroxisomal functions. A re...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2021-04-01
|
| Series: | Frontiers in Cell and Developmental Biology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2021.661298/full |
| _version_ | 1818928162874064896 |
|---|---|
| author | Femke C. C. Klouwer Femke C. C. Klouwer Kim D. Falkenberg Rob Ofman Janet Koster Démi van Gent Sacha Ferdinandusse Ronald J. A. Wanders Hans R. Waterham |
| author_facet | Femke C. C. Klouwer Femke C. C. Klouwer Kim D. Falkenberg Rob Ofman Janet Koster Démi van Gent Sacha Ferdinandusse Ronald J. A. Wanders Hans R. Waterham |
| author_sort | Femke C. C. Klouwer |
| collection | DOAJ |
| description | Peroxisome biogenesis disorders within the Zellweger spectrum (PBD-ZSDs) are most frequently associated with the c.2528G>A (p.G843D) mutation in the PEX1 gene (PEX1-G843D), which results in impaired import of peroxisomal matrix proteins and, consequently, defective peroxisomal functions. A recent study suggested that treatment with autophagy inhibitors, in particular hydroxychloroquine, would be a potential therapeutic option for PBD-ZSD patients carrying the PEX1-G843D mutation. Here, we studied whether autophagy inhibition by chloroquine, hydroxychloroquine and 3-methyladenine indeed can improve peroxisomal functions in four different cell types with the PEX1-G843D mutation, including primary patient cells. Furthermore, we studied whether autophagy inhibition may be the mechanism underlying the previously reported improvement of peroxisomal functions by L-arginine in PEX1-G843D cells. In contrast to L-arginine, we observed no improvement but a worsening of peroxisomal metabolic functions and peroxisomal matrix protein import by the autophagy inhibitors, while genetic knock-down of ATG5 and NBR1 in primary patient cells resulted in only a minimal improvement. Our results do not support the use of autophagy inhibitors as potential treatment for PBD-ZSD patients, whereas L-arginine remains a therapeutically promising compound. |
| first_indexed | 2024-12-20T03:24:32Z |
| format | Article |
| id | doaj.art-714d994559274b5aa2102e279188ee8d |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-12-20T03:24:32Z |
| publishDate | 2021-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-714d994559274b5aa2102e279188ee8d2022-12-21T19:55:08ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2021-04-01910.3389/fcell.2021.661298661298Autophagy Inhibitors Do Not Restore Peroxisomal Functions in Cells With the Most Common Peroxisome Biogenesis DefectFemke C. C. Klouwer0Femke C. C. Klouwer1Kim D. Falkenberg2Rob Ofman3Janet Koster4Démi van Gent5Sacha Ferdinandusse6Ronald J. A. Wanders7Hans R. Waterham8Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology, Endocrinology and Metabolism, Amsterdam University Medical Centers – Location AMC, University of Amsterdam, Amsterdam, NetherlandsDepartment of Pediatric Neurology, Emma Children’s Hospital, Amsterdam University Medical Centers – Location AMC, University of Amsterdam, Amsterdam, NetherlandsLaboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology, Endocrinology and Metabolism, Amsterdam University Medical Centers – Location AMC, University of Amsterdam, Amsterdam, NetherlandsLaboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology, Endocrinology and Metabolism, Amsterdam University Medical Centers – Location AMC, University of Amsterdam, Amsterdam, NetherlandsLaboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology, Endocrinology and Metabolism, Amsterdam University Medical Centers – Location AMC, University of Amsterdam, Amsterdam, NetherlandsLaboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology, Endocrinology and Metabolism, Amsterdam University Medical Centers – Location AMC, University of Amsterdam, Amsterdam, NetherlandsLaboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology, Endocrinology and Metabolism, Amsterdam University Medical Centers – Location AMC, University of Amsterdam, Amsterdam, NetherlandsLaboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology, Endocrinology and Metabolism, Amsterdam University Medical Centers – Location AMC, University of Amsterdam, Amsterdam, NetherlandsLaboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology, Endocrinology and Metabolism, Amsterdam University Medical Centers – Location AMC, University of Amsterdam, Amsterdam, NetherlandsPeroxisome biogenesis disorders within the Zellweger spectrum (PBD-ZSDs) are most frequently associated with the c.2528G>A (p.G843D) mutation in the PEX1 gene (PEX1-G843D), which results in impaired import of peroxisomal matrix proteins and, consequently, defective peroxisomal functions. A recent study suggested that treatment with autophagy inhibitors, in particular hydroxychloroquine, would be a potential therapeutic option for PBD-ZSD patients carrying the PEX1-G843D mutation. Here, we studied whether autophagy inhibition by chloroquine, hydroxychloroquine and 3-methyladenine indeed can improve peroxisomal functions in four different cell types with the PEX1-G843D mutation, including primary patient cells. Furthermore, we studied whether autophagy inhibition may be the mechanism underlying the previously reported improvement of peroxisomal functions by L-arginine in PEX1-G843D cells. In contrast to L-arginine, we observed no improvement but a worsening of peroxisomal metabolic functions and peroxisomal matrix protein import by the autophagy inhibitors, while genetic knock-down of ATG5 and NBR1 in primary patient cells resulted in only a minimal improvement. Our results do not support the use of autophagy inhibitors as potential treatment for PBD-ZSD patients, whereas L-arginine remains a therapeutically promising compound.https://www.frontiersin.org/articles/10.3389/fcell.2021.661298/fullperoxisome biogenesis disorderZellweger spectrum disorderautophagy inhibitorspexophagychloroquinehydroxychloroquine |
| spellingShingle | Femke C. C. Klouwer Femke C. C. Klouwer Kim D. Falkenberg Rob Ofman Janet Koster Démi van Gent Sacha Ferdinandusse Ronald J. A. Wanders Hans R. Waterham Autophagy Inhibitors Do Not Restore Peroxisomal Functions in Cells With the Most Common Peroxisome Biogenesis Defect Frontiers in Cell and Developmental Biology peroxisome biogenesis disorder Zellweger spectrum disorder autophagy inhibitors pexophagy chloroquine hydroxychloroquine |
| title | Autophagy Inhibitors Do Not Restore Peroxisomal Functions in Cells With the Most Common Peroxisome Biogenesis Defect |
| title_full | Autophagy Inhibitors Do Not Restore Peroxisomal Functions in Cells With the Most Common Peroxisome Biogenesis Defect |
| title_fullStr | Autophagy Inhibitors Do Not Restore Peroxisomal Functions in Cells With the Most Common Peroxisome Biogenesis Defect |
| title_full_unstemmed | Autophagy Inhibitors Do Not Restore Peroxisomal Functions in Cells With the Most Common Peroxisome Biogenesis Defect |
| title_short | Autophagy Inhibitors Do Not Restore Peroxisomal Functions in Cells With the Most Common Peroxisome Biogenesis Defect |
| title_sort | autophagy inhibitors do not restore peroxisomal functions in cells with the most common peroxisome biogenesis defect |
| topic | peroxisome biogenesis disorder Zellweger spectrum disorder autophagy inhibitors pexophagy chloroquine hydroxychloroquine |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2021.661298/full |
| work_keys_str_mv | AT femkeccklouwer autophagyinhibitorsdonotrestoreperoxisomalfunctionsincellswiththemostcommonperoxisomebiogenesisdefect AT femkeccklouwer autophagyinhibitorsdonotrestoreperoxisomalfunctionsincellswiththemostcommonperoxisomebiogenesisdefect AT kimdfalkenberg autophagyinhibitorsdonotrestoreperoxisomalfunctionsincellswiththemostcommonperoxisomebiogenesisdefect AT robofman autophagyinhibitorsdonotrestoreperoxisomalfunctionsincellswiththemostcommonperoxisomebiogenesisdefect AT janetkoster autophagyinhibitorsdonotrestoreperoxisomalfunctionsincellswiththemostcommonperoxisomebiogenesisdefect AT demivangent autophagyinhibitorsdonotrestoreperoxisomalfunctionsincellswiththemostcommonperoxisomebiogenesisdefect AT sachaferdinandusse autophagyinhibitorsdonotrestoreperoxisomalfunctionsincellswiththemostcommonperoxisomebiogenesisdefect AT ronaldjawanders autophagyinhibitorsdonotrestoreperoxisomalfunctionsincellswiththemostcommonperoxisomebiogenesisdefect AT hansrwaterham autophagyinhibitorsdonotrestoreperoxisomalfunctionsincellswiththemostcommonperoxisomebiogenesisdefect |