Lysosomal calcium loading promotes spontaneous calcium release by potentiating ryanodine receptors.



Meng, Zhaozheng, Capel, Rebecca A, Bose, Samuel J, Bosch, Erik, de Jong, Sophia, Planque, Robert, Galione, Antony, Burton, Rebecca AB ORCID: 0000-0002-0904-3862 and Bueno-Orovio, Alfonso
(2023) Lysosomal calcium loading promotes spontaneous calcium release by potentiating ryanodine receptors. Biophysical journal, 122 (15). pp. 3044-3059.

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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.

Item Type: Article
Uncontrolled Keywords: Sarcoplasmic Reticulum, Myocytes, Cardiac, Animals, Mice, Disease Models, Animal, Calcium, Ryanodine Receptor Calcium Release Channel, Adrenergic Agents, Calcium Signaling, Arrhythmias, Cardiac
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 09 Apr 2024 14:24
Last Modified: 09 Apr 2024 15:41
DOI: 10.1016/j.bpj.2023.06.007
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3180239