Abstract
Spontaneous calcium release by ryanodine receptors (RyRs) due to intracellular calcium overload results in delayed afterdepolarizations, closely associated with life-threatening arrhythmias. In this regard, inhibiting lysosomal calcium release by two-pore channel 2 (TPC2) knockout has been shown to reduce the incidence of ventricular arrhythmias under β-adrenergic stimulation. However, mechanistic investigations into the role of lysosomal function on RyR spontaneous release remain missing. We investigate the calcium handling mechanisms by which lysosome function modulates RyR spontaneous release, and determine how lysosomes are able to mediate arrhythmias by its influence on calcium loading. Mechanistic studies were conducted using a population of biophysically detailed mouse ventricular models including for the first time modeling of lysosomal function, and calibrated by experimental calcium transients modulated by TPC2. We demonstrate that lysosomal calcium uptake and release can synergistically provide a pathway for fast calcium transport, by which lysosomal calcium release primarily modulates sarcoplasmic reticulum calcium reuptake and RyR release. Enhancement of this lysosomal transport pathway promoted RyR spontaneous release by elevating RyR open probability. In contrast, blocking either lysosomal calcium uptake or release revealed an antiarrhythmic impact. Under conditions of calcium overload, our results indicate that these responses are strongly modulated by intercellular variability in L-type calcium current, RyR release, and sarcoplasmic reticulum calcium-ATPase reuptake. Altogether, our investigations identify that lysosomal calcium handling directly influences RyR spontaneous release by regulating RyR open probability, suggesting antiarrhythmic strategies and identifying key modulators of lysosomal proarrhythmic action.
Original language | English |
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Pages (from-to) | 3044-3059 |
Number of pages | 16 |
Journal | Biophysical Journal |
Volume | 122 |
Issue number | 15 |
Early online date | 15 Jun 2023 |
DOIs | |
Publication status | Published - 8 Aug 2023 |
Bibliographical note
Funding Information:This work is supported by the Sir Henry Dale Wellcome Trust and Royal Society Fellowship ( 109371/Z/15/Z ; to R.A.B.B.) and an Oxford RCF Award. This project was supported by a British Heart Foundation (BHF) Project Grant ( PG/18/4/33521 ). R.A.C. is a Post-doctoral Scientist funded by the Wellcome Trust and Royal Society ( 109371/Z/15/Z ). S.J.B. is a Post-doctoral Scientist funded by the BHF ( PG/18/4/33521 ). A.B.O. acknowledges a BHF Intermediate Basic Science Fellowship ( FS/17/22/32644 ) and an Impact for Infrastructure Award from the National Centre for the Replacement, Refinement and Reduction of Animals in Research ( NC/P001076/1 ). The authors acknowledge additional support from the Oxford BHF Centre of Research Excellence ( RE/13/1/30181 ), and the use of the University of Oxford Advanced Research Computing (ARC) facility ( https://doi.org/10.5281/zenodo.22558 ). For the purpose of Open Access, the authors have applied a CC BY public copyright license to any author accepted manuscript (AAM) version arising from this submission. We thank Prof Derek Terrar for sharing his scientific opinions.
Publisher Copyright:
© 2023 Biophysical Society
Funding
This work is supported by the Sir Henry Dale Wellcome Trust and Royal Society Fellowship ( 109371/Z/15/Z ; to R.A.B.B.) and an Oxford RCF Award. This project was supported by a British Heart Foundation (BHF) Project Grant ( PG/18/4/33521 ). R.A.C. is a Post-doctoral Scientist funded by the Wellcome Trust and Royal Society ( 109371/Z/15/Z ). S.J.B. is a Post-doctoral Scientist funded by the BHF ( PG/18/4/33521 ). A.B.O. acknowledges a BHF Intermediate Basic Science Fellowship ( FS/17/22/32644 ) and an Impact for Infrastructure Award from the National Centre for the Replacement, Refinement and Reduction of Animals in Research ( NC/P001076/1 ). The authors acknowledge additional support from the Oxford BHF Centre of Research Excellence ( RE/13/1/30181 ), and the use of the University of Oxford Advanced Research Computing (ARC) facility ( https://doi.org/10.5281/zenodo.22558 ). For the purpose of Open Access, the authors have applied a CC BY public copyright license to any author accepted manuscript (AAM) version arising from this submission. We thank Prof Derek Terrar for sharing his scientific opinions.
Keywords
- calcium handling
- lysosomes
- modeling and simulation
- β-adrenergic stimulation