The RyR2-R2474S Mutation Sensitizes Cardiomyocytes and Hearts to Catecholaminergic Stress-Induced Oxidation of the Mitochondrial Glutathione Pool
Missense mutations in the cardiac ryanodine receptor type 2 (RyR2) characteristically cause catecholaminergic arrhythmias. Reminiscent of the phenotype in patients, RyR2-R2474S knockin mice develop exercise-induced ventricular tachyarrhythmias. In cardiomyocytes, increased mitochondrial matrix Ca2+...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2021-12-01
|
| Series: | Frontiers in Physiology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fphys.2021.777770/full |
| _version_ | 1818353399991631872 |
|---|---|
| author | Jörg W. Wegener Jörg W. Wegener Jörg W. Wegener Ahmed Wagdi Ahmed Wagdi Eva Wagner Dörthe M. Katschinski Dörthe M. Katschinski Gerd Hasenfuss Gerd Hasenfuss Tobias Bruegmann Tobias Bruegmann Tobias Bruegmann Stephan E. Lehnart Stephan E. Lehnart Stephan E. Lehnart |
| author_facet | Jörg W. Wegener Jörg W. Wegener Jörg W. Wegener Ahmed Wagdi Ahmed Wagdi Eva Wagner Dörthe M. Katschinski Dörthe M. Katschinski Gerd Hasenfuss Gerd Hasenfuss Tobias Bruegmann Tobias Bruegmann Tobias Bruegmann Stephan E. Lehnart Stephan E. Lehnart Stephan E. Lehnart |
| author_sort | Jörg W. Wegener |
| collection | DOAJ |
| description | Missense mutations in the cardiac ryanodine receptor type 2 (RyR2) characteristically cause catecholaminergic arrhythmias. Reminiscent of the phenotype in patients, RyR2-R2474S knockin mice develop exercise-induced ventricular tachyarrhythmias. In cardiomyocytes, increased mitochondrial matrix Ca2+ uptake was recently linked to non-linearly enhanced ATP synthesis with important implications for cardiac redox metabolism. We hypothesize that catecholaminergic stimulation and contractile activity amplify mitochondrial oxidation pathologically in RyR2-R2474S cardiomyocytes. To investigate this question, we generated double transgenic RyR2-R2474S mice expressing a mitochondria-restricted fluorescent biosensor to monitor the glutathione redox potential (EGSH). Electrical field pacing-evoked RyR2-WT and RyR2-R2474S cardiomyocyte contractions resulted in a small but significant baseline EGSH increase. Importantly, β-adrenergic stimulation resulted in excessive EGSH oxidization of the mitochondrial matrix in RyR2-R2474S cardiomyocytes compared to baseline and RyR2-WT control. Physiologically β-adrenergic stimulation significantly increased mitochondrial EGSH further in intact beating RyR2-R2474S but not in RyR2-WT control Langendorff perfused hearts. Finally, this catecholaminergic EGSH increase was significantly attenuated following treatment with the RyR2 channel blocker dantrolene. Together, catecholaminergic stimulation and increased diastolic Ca2+ leak induce a strong, but dantrolene-inhibited mitochondrial EGSH oxidization in RyR2-R2474S cardiomyocytes. |
| first_indexed | 2024-12-13T19:08:55Z |
| format | Article |
| id | doaj.art-710f973264f24e6d879ff31f3f3c4fa1 |
| institution | Directory Open Access Journal |
| issn | 1664-042X |
| language | English |
| last_indexed | 2024-12-13T19:08:55Z |
| publishDate | 2021-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Physiology |
| spelling | doaj.art-710f973264f24e6d879ff31f3f3c4fa12022-12-21T23:34:28ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2021-12-011210.3389/fphys.2021.777770777770The RyR2-R2474S Mutation Sensitizes Cardiomyocytes and Hearts to Catecholaminergic Stress-Induced Oxidation of the Mitochondrial Glutathione PoolJörg W. Wegener0Jörg W. Wegener1Jörg W. Wegener2Ahmed Wagdi3Ahmed Wagdi4Eva Wagner5Dörthe M. Katschinski6Dörthe M. Katschinski7Gerd Hasenfuss8Gerd Hasenfuss9Tobias Bruegmann10Tobias Bruegmann11Tobias Bruegmann12Stephan E. Lehnart13Stephan E. Lehnart14Stephan E. Lehnart15Department of Cardiology and Pulmonology, Heart Research Center Göttingen, University Medical Center Göttingen, Georg August University of Göttingen, Göttingen, GermanyCluster of Excellence “Multiscale Bioimaging: From Molecular Machines to Networks of Excitable Cells” (MBExC), Georg-August University of Göttingen, Göttingen, GermanyDZHK (German Centre for Cardiovascular Research), Partner Site Göttingen, Göttingen, GermanyDZHK (German Centre for Cardiovascular Research), Partner Site Göttingen, Göttingen, GermanyInstitute of Cardiovascular Physiology, University Medical Center Göttingen, Georg August University of Göttingen, Göttingen, GermanyDepartment of Cardiology and Pulmonology, Heart Research Center Göttingen, University Medical Center Göttingen, Georg August University of Göttingen, Göttingen, GermanyDZHK (German Centre for Cardiovascular Research), Partner Site Göttingen, Göttingen, GermanyInstitute of Cardiovascular Physiology, University Medical Center Göttingen, Georg August University of Göttingen, Göttingen, GermanyDepartment of Cardiology and Pulmonology, Heart Research Center Göttingen, University Medical Center Göttingen, Georg August University of Göttingen, Göttingen, GermanyDZHK (German Centre for Cardiovascular Research), Partner Site Göttingen, Göttingen, GermanyCluster of Excellence “Multiscale Bioimaging: From Molecular Machines to Networks of Excitable Cells” (MBExC), Georg-August University of Göttingen, Göttingen, GermanyDZHK (German Centre for Cardiovascular Research), Partner Site Göttingen, Göttingen, GermanyInstitute of Cardiovascular Physiology, University Medical Center Göttingen, Georg August University of Göttingen, Göttingen, GermanyDepartment of Cardiology and Pulmonology, Heart Research Center Göttingen, University Medical Center Göttingen, Georg August University of Göttingen, Göttingen, GermanyCluster of Excellence “Multiscale Bioimaging: From Molecular Machines to Networks of Excitable Cells” (MBExC), Georg-August University of Göttingen, Göttingen, GermanyDZHK (German Centre for Cardiovascular Research), Partner Site Göttingen, Göttingen, GermanyMissense mutations in the cardiac ryanodine receptor type 2 (RyR2) characteristically cause catecholaminergic arrhythmias. Reminiscent of the phenotype in patients, RyR2-R2474S knockin mice develop exercise-induced ventricular tachyarrhythmias. In cardiomyocytes, increased mitochondrial matrix Ca2+ uptake was recently linked to non-linearly enhanced ATP synthesis with important implications for cardiac redox metabolism. We hypothesize that catecholaminergic stimulation and contractile activity amplify mitochondrial oxidation pathologically in RyR2-R2474S cardiomyocytes. To investigate this question, we generated double transgenic RyR2-R2474S mice expressing a mitochondria-restricted fluorescent biosensor to monitor the glutathione redox potential (EGSH). Electrical field pacing-evoked RyR2-WT and RyR2-R2474S cardiomyocyte contractions resulted in a small but significant baseline EGSH increase. Importantly, β-adrenergic stimulation resulted in excessive EGSH oxidization of the mitochondrial matrix in RyR2-R2474S cardiomyocytes compared to baseline and RyR2-WT control. Physiologically β-adrenergic stimulation significantly increased mitochondrial EGSH further in intact beating RyR2-R2474S but not in RyR2-WT control Langendorff perfused hearts. Finally, this catecholaminergic EGSH increase was significantly attenuated following treatment with the RyR2 channel blocker dantrolene. Together, catecholaminergic stimulation and increased diastolic Ca2+ leak induce a strong, but dantrolene-inhibited mitochondrial EGSH oxidization in RyR2-R2474S cardiomyocytes.https://www.frontiersin.org/articles/10.3389/fphys.2021.777770/fullryanodine receptormitochondriadantroleneglutathione redox potentialRyR2 Ca2+ leakmitochondrial oxidation |
| spellingShingle | Jörg W. Wegener Jörg W. Wegener Jörg W. Wegener Ahmed Wagdi Ahmed Wagdi Eva Wagner Dörthe M. Katschinski Dörthe M. Katschinski Gerd Hasenfuss Gerd Hasenfuss Tobias Bruegmann Tobias Bruegmann Tobias Bruegmann Stephan E. Lehnart Stephan E. Lehnart Stephan E. Lehnart The RyR2-R2474S Mutation Sensitizes Cardiomyocytes and Hearts to Catecholaminergic Stress-Induced Oxidation of the Mitochondrial Glutathione Pool Frontiers in Physiology ryanodine receptor mitochondria dantrolene glutathione redox potential RyR2 Ca2+ leak mitochondrial oxidation |
| title | The RyR2-R2474S Mutation Sensitizes Cardiomyocytes and Hearts to Catecholaminergic Stress-Induced Oxidation of the Mitochondrial Glutathione Pool |
| title_full | The RyR2-R2474S Mutation Sensitizes Cardiomyocytes and Hearts to Catecholaminergic Stress-Induced Oxidation of the Mitochondrial Glutathione Pool |
| title_fullStr | The RyR2-R2474S Mutation Sensitizes Cardiomyocytes and Hearts to Catecholaminergic Stress-Induced Oxidation of the Mitochondrial Glutathione Pool |
| title_full_unstemmed | The RyR2-R2474S Mutation Sensitizes Cardiomyocytes and Hearts to Catecholaminergic Stress-Induced Oxidation of the Mitochondrial Glutathione Pool |
| title_short | The RyR2-R2474S Mutation Sensitizes Cardiomyocytes and Hearts to Catecholaminergic Stress-Induced Oxidation of the Mitochondrial Glutathione Pool |
| title_sort | ryr2 r2474s mutation sensitizes cardiomyocytes and hearts to catecholaminergic stress induced oxidation of the mitochondrial glutathione pool |
| topic | ryanodine receptor mitochondria dantrolene glutathione redox potential RyR2 Ca2+ leak mitochondrial oxidation |
| url | https://www.frontiersin.org/articles/10.3389/fphys.2021.777770/full |
| work_keys_str_mv | AT jorgwwegener theryr2r2474smutationsensitizescardiomyocytesandheartstocatecholaminergicstressinducedoxidationofthemitochondrialglutathionepool AT jorgwwegener theryr2r2474smutationsensitizescardiomyocytesandheartstocatecholaminergicstressinducedoxidationofthemitochondrialglutathionepool AT jorgwwegener theryr2r2474smutationsensitizescardiomyocytesandheartstocatecholaminergicstressinducedoxidationofthemitochondrialglutathionepool AT ahmedwagdi theryr2r2474smutationsensitizescardiomyocytesandheartstocatecholaminergicstressinducedoxidationofthemitochondrialglutathionepool AT ahmedwagdi theryr2r2474smutationsensitizescardiomyocytesandheartstocatecholaminergicstressinducedoxidationofthemitochondrialglutathionepool AT evawagner theryr2r2474smutationsensitizescardiomyocytesandheartstocatecholaminergicstressinducedoxidationofthemitochondrialglutathionepool AT dorthemkatschinski theryr2r2474smutationsensitizescardiomyocytesandheartstocatecholaminergicstressinducedoxidationofthemitochondrialglutathionepool AT dorthemkatschinski theryr2r2474smutationsensitizescardiomyocytesandheartstocatecholaminergicstressinducedoxidationofthemitochondrialglutathionepool AT gerdhasenfuss theryr2r2474smutationsensitizescardiomyocytesandheartstocatecholaminergicstressinducedoxidationofthemitochondrialglutathionepool AT gerdhasenfuss theryr2r2474smutationsensitizescardiomyocytesandheartstocatecholaminergicstressinducedoxidationofthemitochondrialglutathionepool AT tobiasbruegmann theryr2r2474smutationsensitizescardiomyocytesandheartstocatecholaminergicstressinducedoxidationofthemitochondrialglutathionepool AT tobiasbruegmann theryr2r2474smutationsensitizescardiomyocytesandheartstocatecholaminergicstressinducedoxidationofthemitochondrialglutathionepool AT tobiasbruegmann theryr2r2474smutationsensitizescardiomyocytesandheartstocatecholaminergicstressinducedoxidationofthemitochondrialglutathionepool AT stephanelehnart theryr2r2474smutationsensitizescardiomyocytesandheartstocatecholaminergicstressinducedoxidationofthemitochondrialglutathionepool AT stephanelehnart theryr2r2474smutationsensitizescardiomyocytesandheartstocatecholaminergicstressinducedoxidationofthemitochondrialglutathionepool AT stephanelehnart theryr2r2474smutationsensitizescardiomyocytesandheartstocatecholaminergicstressinducedoxidationofthemitochondrialglutathionepool AT jorgwwegener ryr2r2474smutationsensitizescardiomyocytesandheartstocatecholaminergicstressinducedoxidationofthemitochondrialglutathionepool AT jorgwwegener ryr2r2474smutationsensitizescardiomyocytesandheartstocatecholaminergicstressinducedoxidationofthemitochondrialglutathionepool AT jorgwwegener ryr2r2474smutationsensitizescardiomyocytesandheartstocatecholaminergicstressinducedoxidationofthemitochondrialglutathionepool AT ahmedwagdi ryr2r2474smutationsensitizescardiomyocytesandheartstocatecholaminergicstressinducedoxidationofthemitochondrialglutathionepool AT ahmedwagdi ryr2r2474smutationsensitizescardiomyocytesandheartstocatecholaminergicstressinducedoxidationofthemitochondrialglutathionepool AT evawagner ryr2r2474smutationsensitizescardiomyocytesandheartstocatecholaminergicstressinducedoxidationofthemitochondrialglutathionepool AT dorthemkatschinski ryr2r2474smutationsensitizescardiomyocytesandheartstocatecholaminergicstressinducedoxidationofthemitochondrialglutathionepool AT dorthemkatschinski ryr2r2474smutationsensitizescardiomyocytesandheartstocatecholaminergicstressinducedoxidationofthemitochondrialglutathionepool AT gerdhasenfuss ryr2r2474smutationsensitizescardiomyocytesandheartstocatecholaminergicstressinducedoxidationofthemitochondrialglutathionepool AT gerdhasenfuss ryr2r2474smutationsensitizescardiomyocytesandheartstocatecholaminergicstressinducedoxidationofthemitochondrialglutathionepool AT tobiasbruegmann ryr2r2474smutationsensitizescardiomyocytesandheartstocatecholaminergicstressinducedoxidationofthemitochondrialglutathionepool AT tobiasbruegmann ryr2r2474smutationsensitizescardiomyocytesandheartstocatecholaminergicstressinducedoxidationofthemitochondrialglutathionepool AT tobiasbruegmann ryr2r2474smutationsensitizescardiomyocytesandheartstocatecholaminergicstressinducedoxidationofthemitochondrialglutathionepool AT stephanelehnart ryr2r2474smutationsensitizescardiomyocytesandheartstocatecholaminergicstressinducedoxidationofthemitochondrialglutathionepool AT stephanelehnart ryr2r2474smutationsensitizescardiomyocytesandheartstocatecholaminergicstressinducedoxidationofthemitochondrialglutathionepool AT stephanelehnart ryr2r2474smutationsensitizescardiomyocytesandheartstocatecholaminergicstressinducedoxidationofthemitochondrialglutathionepool |