Metabolic switch from fatty acid oxidation to glycolysis in knock‐in mouse model of Barth syndrome
Abstract Mitochondria are central for cellular metabolism and energy supply. Barth syndrome (BTHS) is a severe disorder, due to dysfunction of the mitochondrial cardiolipin acyl transferase tafazzin. Altered cardiolipin remodeling affects mitochondrial inner membrane organization and function of mem...
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| Format: | Article |
| Language: | English |
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Springer Nature
2023-08-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.202317399 |
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| author | Arpita Chowdhury Angela Boshnakovska Abhishek Aich Aditi Methi Ana Maria Vergel Leon Ivan Silbern Christian Lüchtenborg Lukas Cyganek Jan Prochazka Radislav Sedlacek Jiri Lindovsky Dominic Wachs Zuzana Nichtova Dagmar Zudova Gizela Koubkova André Fischer Henning Urlaub Britta Brügger Dörthe M Katschinski Jan Dudek Peter Rehling |
| author_facet | Arpita Chowdhury Angela Boshnakovska Abhishek Aich Aditi Methi Ana Maria Vergel Leon Ivan Silbern Christian Lüchtenborg Lukas Cyganek Jan Prochazka Radislav Sedlacek Jiri Lindovsky Dominic Wachs Zuzana Nichtova Dagmar Zudova Gizela Koubkova André Fischer Henning Urlaub Britta Brügger Dörthe M Katschinski Jan Dudek Peter Rehling |
| author_sort | Arpita Chowdhury |
| collection | DOAJ |
| description | Abstract Mitochondria are central for cellular metabolism and energy supply. Barth syndrome (BTHS) is a severe disorder, due to dysfunction of the mitochondrial cardiolipin acyl transferase tafazzin. Altered cardiolipin remodeling affects mitochondrial inner membrane organization and function of membrane proteins such as transporters and the oxidative phosphorylation (OXPHOS) system. Here, we describe a mouse model that carries a G197V exchange in tafazzin, corresponding to BTHS patients. TAZG197V mice recapitulate disease‐specific pathology including cardiac dysfunction and reduced oxidative phosphorylation. We show that mutant mitochondria display defective fatty acid‐driven oxidative phosphorylation due to reduced levels of carnitine palmitoyl transferases. A metabolic switch in ATP production from OXPHOS to glycolysis is apparent in mouse heart and patient iPSC cell‐derived cardiomyocytes. An increase in glycolytic ATP production inactivates AMPK causing altered metabolic signaling in TAZG197V. Treatment of mutant cells with AMPK activator reestablishes fatty acid‐driven OXPHOS and protects mice against cardiac dysfunction. |
| format | Article |
| id | doaj-art-d06b0aeb0b084c3dae36b33896fa43c5 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2023-08-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-d06b0aeb0b084c3dae36b33896fa43c52025-08-20T04:02:54ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842023-08-0115912110.15252/emmm.202317399Metabolic switch from fatty acid oxidation to glycolysis in knock‐in mouse model of Barth syndromeArpita Chowdhury0Angela Boshnakovska1Abhishek Aich2Aditi Methi3Ana Maria Vergel Leon4Ivan Silbern5Christian Lüchtenborg6Lukas Cyganek7Jan Prochazka8Radislav Sedlacek9Jiri Lindovsky10Dominic Wachs11Zuzana Nichtova12Dagmar Zudova13Gizela Koubkova14André Fischer15Henning Urlaub16Britta Brügger17Dörthe M Katschinski18Jan Dudek19Peter Rehling20Department of Cellular Biochemistry, University Medical Center GöttingenDepartment of Cellular Biochemistry, University Medical Center GöttingenDepartment of Cellular Biochemistry, University Medical Center GöttingenDepartment of Psychiatry and Psychotherapy, University Medical Center GöttingenDepartment of Cardiovascular Physiology, University Medical Center GöttingenThe Bioanalytical Mass Spectrometry Group, Max Planck Institute for Multidisciplinary SciencesHeidelberg University Biochemistry Center (BZH)Cluster of Excellence “Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells” (MBExC), University of GöttingenCzech Centre for Phenogenomics, Institute of Molecular Genetics of the CASCzech Centre for Phenogenomics, Institute of Molecular Genetics of the CASCzech Centre for Phenogenomics, Institute of Molecular Genetics of the CASDepartment of Cellular Biochemistry, University Medical Center GöttingenCzech Centre for Phenogenomics, Institute of Molecular Genetics of the CASCzech Centre for Phenogenomics, Institute of Molecular Genetics of the CASCzech Centre for Phenogenomics, Institute of Molecular Genetics of the CASCluster of Excellence “Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells” (MBExC), University of GöttingenThe Bioanalytical Mass Spectrometry Group, Max Planck Institute for Multidisciplinary SciencesHeidelberg University Biochemistry Center (BZH)Department of Cardiovascular Physiology, University Medical Center GöttingenDepartment of Cellular Biochemistry, University Medical Center GöttingenDepartment of Cellular Biochemistry, University Medical Center GöttingenAbstract Mitochondria are central for cellular metabolism and energy supply. Barth syndrome (BTHS) is a severe disorder, due to dysfunction of the mitochondrial cardiolipin acyl transferase tafazzin. Altered cardiolipin remodeling affects mitochondrial inner membrane organization and function of membrane proteins such as transporters and the oxidative phosphorylation (OXPHOS) system. Here, we describe a mouse model that carries a G197V exchange in tafazzin, corresponding to BTHS patients. TAZG197V mice recapitulate disease‐specific pathology including cardiac dysfunction and reduced oxidative phosphorylation. We show that mutant mitochondria display defective fatty acid‐driven oxidative phosphorylation due to reduced levels of carnitine palmitoyl transferases. A metabolic switch in ATP production from OXPHOS to glycolysis is apparent in mouse heart and patient iPSC cell‐derived cardiomyocytes. An increase in glycolytic ATP production inactivates AMPK causing altered metabolic signaling in TAZG197V. Treatment of mutant cells with AMPK activator reestablishes fatty acid‐driven OXPHOS and protects mice against cardiac dysfunction.https://doi.org/10.15252/emmm.202317399Barth syndromecardiolipincardiomyopathymitochondriatafazzin |
| spellingShingle | Arpita Chowdhury Angela Boshnakovska Abhishek Aich Aditi Methi Ana Maria Vergel Leon Ivan Silbern Christian Lüchtenborg Lukas Cyganek Jan Prochazka Radislav Sedlacek Jiri Lindovsky Dominic Wachs Zuzana Nichtova Dagmar Zudova Gizela Koubkova André Fischer Henning Urlaub Britta Brügger Dörthe M Katschinski Jan Dudek Peter Rehling Metabolic switch from fatty acid oxidation to glycolysis in knock‐in mouse model of Barth syndrome EMBO Molecular Medicine Barth syndrome cardiolipin cardiomyopathy mitochondria tafazzin |
| title | Metabolic switch from fatty acid oxidation to glycolysis in knock‐in mouse model of Barth syndrome |
| title_full | Metabolic switch from fatty acid oxidation to glycolysis in knock‐in mouse model of Barth syndrome |
| title_fullStr | Metabolic switch from fatty acid oxidation to glycolysis in knock‐in mouse model of Barth syndrome |
| title_full_unstemmed | Metabolic switch from fatty acid oxidation to glycolysis in knock‐in mouse model of Barth syndrome |
| title_short | Metabolic switch from fatty acid oxidation to glycolysis in knock‐in mouse model of Barth syndrome |
| title_sort | metabolic switch from fatty acid oxidation to glycolysis in knock in mouse model of barth syndrome |
| topic | Barth syndrome cardiolipin cardiomyopathy mitochondria tafazzin |
| url | https://doi.org/10.15252/emmm.202317399 |
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