The RyR2-R2474S Mutation Sensitizes Cardiomyocytes and Hearts to Catecholaminergic Stress-Induced Oxidation of the Mitochondrial Glutathione Pool
2021-12-09 | journal article; research paper. A publication with affiliation to the University of Göttingen.
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The RyR2-R2474S Mutation Sensitizes Cardiomyocytes and Hearts to Catecholaminergic Stress-Induced Oxidation of the Mitochondrial Glutathione Pool
Wegener, J. W.; Wagdi, A.; Wagner, E.; Katschinski, D. M.; Hasenfuß, G. ; Brügmann, T. & Lehnart, S. E. (2021)
Frontiers in Physiology, 12. DOI: https://doi.org/10.3389/fphys.2021.777770
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Details
- Authors
- Wegener, Jörg W.; Wagdi, Ahmed; Wagner, Eva; Katschinski, Dörthe M.; Hasenfuß, Gerd ; Brügmann, Tobias ; Lehnart, Stephan E.
- Abstract
- 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.
- Issue Date
- 9-December-2021
- Journal
- Frontiers in Physiology
- Project
- EXC 2067: Multiscale Bioimaging
SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz
SFB 1002 | A09: Lokale molekulare Nanodomänen-Regulation der kardialen Ryanodin-Rezeptor-Funktion
SFB 1002 | S02: Hochauflösende Fluoreszenzmikroskopie und integrative Datenanalyse - Working Group
- RG Lehnart
RG Brügmann (Vegetative Optogenetik)
RG Hasenfuß (Transition zur Herzinsuffizienz) - Language
- English