Renal phenotyping in a hypomorphic murine model of propionic aciduria reveals common pathomechanisms in organic acidurias
Abstract Mutations in the mitochondrial enzyme propionyl-CoA carboxylase (PCC) cause propionic aciduria (PA). Chronic kidney disease (CKD) is a known long-term complication. However, good metabolic control and standard therapy fail to prevent CKD. The pathophysiological mechanisms of CKD are unclear...
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Nature Portfolio
2024-12-01
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| Online Access: | https://doi.org/10.1038/s41598-024-79572-z |
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| author | Anke Schumann Ainhoa Martinez-Pizarro Eva Richard Christoph Schell Anna Laura Kössinger Karina A. Zeyer Stefan Tholen Oliver Schilling Michael Barry Björn Neubauer Michael Köttgen Luciana Hannibal Lourdes R. Desviat Ute Spiekerkötter |
| author_facet | Anke Schumann Ainhoa Martinez-Pizarro Eva Richard Christoph Schell Anna Laura Kössinger Karina A. Zeyer Stefan Tholen Oliver Schilling Michael Barry Björn Neubauer Michael Köttgen Luciana Hannibal Lourdes R. Desviat Ute Spiekerkötter |
| author_sort | Anke Schumann |
| collection | DOAJ |
| description | Abstract Mutations in the mitochondrial enzyme propionyl-CoA carboxylase (PCC) cause propionic aciduria (PA). Chronic kidney disease (CKD) is a known long-term complication. However, good metabolic control and standard therapy fail to prevent CKD. The pathophysiological mechanisms of CKD are unclear. We investigated the renal phenotype of a hypomorphic murine PA model (Pcca -/- (A138T)) to identify CKD-driving mechanisms. Pcca -/- (A138T) mice show elevated retention parameters and express markers of kidney damage progressing with time. Morphological assessment of the Pcca -/- (A138T) mouse kidneys indicated partial flattening of tubular epithelial cells and focal tubular-cystic dilation. We observed altered renal mitochondrial ultrastructure and mechanisms acting against oxidative stress were active. LC–MS/MS analysis confirmed disease-specific metabolic signatures and revealed disturbances in mitochondrial energy generation via the TCA cycle. Our investigations revealed altered mitochondrial networks shifted towards fission and a marked reduction of mitophagy. We observed a steep reduction of PGC-1-α, the key mediator modulating mitochondrial functions and a counter actor of mitochondrial fission. Our results suggest that impairment of mitochondrial homeostasis and quality control are involved in CKD development in PA. Therapeutic targeting of the identified pathways might help to ameliorate CKD in addition to the current treatment strategies. |
| format | Article |
| id | doaj-art-4c32136c6d9648c19a39322aa18f4e7c |
| institution | OA Journals |
| issn | 2045-2322 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-4c32136c6d9648c19a39322aa18f4e7c2025-08-20T02:31:46ZengNature PortfolioScientific Reports2045-23222024-12-0114111210.1038/s41598-024-79572-zRenal phenotyping in a hypomorphic murine model of propionic aciduria reveals common pathomechanisms in organic aciduriasAnke Schumann0Ainhoa Martinez-Pizarro1Eva Richard2Christoph Schell3Anna Laura Kössinger4Karina A. Zeyer5Stefan Tholen6Oliver Schilling7Michael Barry8Björn Neubauer9Michael Köttgen10Luciana Hannibal11Lourdes R. Desviat12Ute Spiekerkötter13Department of General Paediatrics, Adolescent Medicine and Neonatology, Faculty of Medicine, Medical Center, University of FreiburgCentro de Biología Molecular Severo Ochoa, UAM-CSIC, CIBERER, IdiPaz, IUBM, Universidad Autónoma de MadridCentro de Biología Molecular Severo Ochoa, UAM-CSIC, CIBERER, IdiPaz, IUBM, Universidad Autónoma de MadridFaculty of Medicine, Medical Center, University of Freiburg, Institute for Surgical PathologyFaculty of Medicine, Medical Center, University of Freiburg, Institute for Surgical PathologyDepartment of General Paediatrics, Adolescent Medicine and Neonatology, Faculty of Medicine, Medical Center, University of FreiburgFaculty of Medicine, Medical Center, University of Freiburg, Institute for Surgical PathologyFaculty of Medicine, Medical Center, University of Freiburg, Institute for Surgical PathologyDepartment of Medicine, Division of Infectious Diseases, Mayo ClinicDepartment of Medicine IV - Nephrology and Primary Care, Faculty of Medicine and Medical Center, University of FreiburgDepartment of Medicine IV - Nephrology and Primary Care, Faculty of Medicine and Medical Center, University of FreiburgDepartment of General Paediatrics, Adolescent Medicine and Neonatology, Laboratory of Clinical Biochemistry and Metabolism, Faculty of Medicine, Medical Center, University of FreiburgCentro de Biología Molecular Severo Ochoa, UAM-CSIC, CIBERER, IdiPaz, IUBM, Universidad Autónoma de MadridDepartment of General Paediatrics, Adolescent Medicine and Neonatology, Faculty of Medicine, Medical Center, University of FreiburgAbstract Mutations in the mitochondrial enzyme propionyl-CoA carboxylase (PCC) cause propionic aciduria (PA). Chronic kidney disease (CKD) is a known long-term complication. However, good metabolic control and standard therapy fail to prevent CKD. The pathophysiological mechanisms of CKD are unclear. We investigated the renal phenotype of a hypomorphic murine PA model (Pcca -/- (A138T)) to identify CKD-driving mechanisms. Pcca -/- (A138T) mice show elevated retention parameters and express markers of kidney damage progressing with time. Morphological assessment of the Pcca -/- (A138T) mouse kidneys indicated partial flattening of tubular epithelial cells and focal tubular-cystic dilation. We observed altered renal mitochondrial ultrastructure and mechanisms acting against oxidative stress were active. LC–MS/MS analysis confirmed disease-specific metabolic signatures and revealed disturbances in mitochondrial energy generation via the TCA cycle. Our investigations revealed altered mitochondrial networks shifted towards fission and a marked reduction of mitophagy. We observed a steep reduction of PGC-1-α, the key mediator modulating mitochondrial functions and a counter actor of mitochondrial fission. Our results suggest that impairment of mitochondrial homeostasis and quality control are involved in CKD development in PA. Therapeutic targeting of the identified pathways might help to ameliorate CKD in addition to the current treatment strategies.https://doi.org/10.1038/s41598-024-79572-zPropionic aciduriaMitochondrial dysfunctionMitochondrial homeostasisMitochondrial fissionChronic kidney diseaseMitochondrial energy metabolism |
| spellingShingle | Anke Schumann Ainhoa Martinez-Pizarro Eva Richard Christoph Schell Anna Laura Kössinger Karina A. Zeyer Stefan Tholen Oliver Schilling Michael Barry Björn Neubauer Michael Köttgen Luciana Hannibal Lourdes R. Desviat Ute Spiekerkötter Renal phenotyping in a hypomorphic murine model of propionic aciduria reveals common pathomechanisms in organic acidurias Scientific Reports Propionic aciduria Mitochondrial dysfunction Mitochondrial homeostasis Mitochondrial fission Chronic kidney disease Mitochondrial energy metabolism |
| title | Renal phenotyping in a hypomorphic murine model of propionic aciduria reveals common pathomechanisms in organic acidurias |
| title_full | Renal phenotyping in a hypomorphic murine model of propionic aciduria reveals common pathomechanisms in organic acidurias |
| title_fullStr | Renal phenotyping in a hypomorphic murine model of propionic aciduria reveals common pathomechanisms in organic acidurias |
| title_full_unstemmed | Renal phenotyping in a hypomorphic murine model of propionic aciduria reveals common pathomechanisms in organic acidurias |
| title_short | Renal phenotyping in a hypomorphic murine model of propionic aciduria reveals common pathomechanisms in organic acidurias |
| title_sort | renal phenotyping in a hypomorphic murine model of propionic aciduria reveals common pathomechanisms in organic acidurias |
| topic | Propionic aciduria Mitochondrial dysfunction Mitochondrial homeostasis Mitochondrial fission Chronic kidney disease Mitochondrial energy metabolism |
| url | https://doi.org/10.1038/s41598-024-79572-z |
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