bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2022.11.09.515777

Lysosomal calcium loading promotes arrhythmias by potentiating ryanodine receptor release

Meng, Z.·Capel, R.-A.·Bose, S. J.·Bosch, E.·Jong, S. d.·Planque, R.·Galione, A.·Burton, R. A.·Bueno-Orovio, A.
View original source ↗Export metadata ↓

Abstract

Spontaneous calcium release by ryanodine receptors (RyRs) due to intracellular calcium overload results in delayed afterdepolarisations, 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 {beta}-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 modelling of lysosomal function, and calibrated by experimental calcium transients modulated by TPC2. We demonstrate that lysosomal calcium uptake and release can synergistically provide a buffering pathway of fast calcium transport, by which lysosomal calcium release primarily modulates sarcoplasmic reticulum (SR) calcium reuptake and RyR release. Enhancement of this lysosomal transport pathway promoted RyR spontaneous release by elevating the SR-junction calcium gradient. 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 SERCA reuptake. Altogether, our investigations identify that lysosomal calcium handling directly influences RyR spontaneous release by regulating the SR-junction calcium gradient, suggesting antiarrhythmic strategies and identifying key modulators of lysosomal proarrhythmic action. Statement of SignificanceDelayed afterdepolarisations arising from spontaneous RyR calcium release are an important risk factor for arrhythmogenesis. Inhibiting lysosomal calcium release by TPC2-KO reduces the propensity for ventricular arrhythmias. However, understanding downstream effects of lysosomal calcium release on spontaneous RyR release is lacking. Understanding lysosomes as arrhythmia sources requires alternative approaches to controlled laboratory techniques: these restrain variability experimentally and statistically. Our study presents two methodological novelties by focusing on calibration with experimental findings using a population of biophysically-detailed models and incorporating lysosomal mechanisms. Lysosomal calcium handling promotes RyR spontaneous release by elevating the SR-junction calcium gradient. Blocking lysosomal function uncovers an antiarrhythmic strategy. Lysosome-release proarrhythmic risk is determined by synergistic enhancements of lysosomal uptake with RyR release or L-type calcium current.

Explore related subjects

biophysicsPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Meng, Z., Capel, R.-A., Bose, S. J., Bosch, E., Jong, S. d., Planque, R., Galione, A., Burton, R. A., Bueno-Orovio, A.. 2022-11-09. Lysosomal calcium loading promotes arrhythmias by potentiating ryanodine receptor release. https://doi.org/10.1101/2022.11.09.515777

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Design of colipids with controlled lateral distance of head group moieties for targeting strategies in the field of lipid-based nanoparticles

Lipid nanoparticles and liposomes are nanoparticle drug formulations which are firmly established in clinics. In order to expand their application and improve efficacy, surface modifications can be a key strategy, especially for cell specific targeting. Targeting can be achieved by integrating ligand functionalized lipids or lipidoids on the nanoparticle surface. In this case, not solely the targeting ligand itself, but also the structure of the whole targeting lipid/lipidoid can affect the interaction of the targeting ligand with the binding motive on cells. Especially, distal spacer structures between lipid anchor and ligand unit, often composed of polyethylene glycol chains, provide a certain distance of the ligand from the nanoparticle surface. A concept which is currently neglected is the control of the lateral distance between ligand structures on the nanoparticle. Herein we investigated the possibility to design lipidoids with a lateral spacer composed of polyethylene glycol units. We synthesized and characterized different lipidoids which provide a primary amine in the head group for possible ligand coupling. In our model lipidoids the head groups were functionalized with a paramagnetic probe to apply electron paramagnetic resonance (EPR) methods for the characterization of the lipidoid interaction with model nanoparticles, in our case liposomes. Continuous wave EPR was used to study the efficiency of the novel lipidoids to integrate into lipid bilayers of model liposomes, which was shown to depend on lipidoid structure and liposome composition. Furthermore, using double electron-electron resonance (DEER), we observed lipidoid conformational changes occurring upon integration into liposomes.

biophysics↗
bioRxiv2026

Beyond Sequence and Structure: Pretraining PLMs on Continuous Biophysical Fields

We introduce the Biophysical Transformer, a protein language model that adds continuous biophysical fields as a third pretraining signal beside sequence and structure. A Poisson-Boltzmann solver computes the electrostatic potential around each three-residue token, and the model learns to predict it from sequence alone. A rotationally invariant spherical-harmonic descriptor serves as the loss target, eliminating the need for frame alignment during training and for coordinates at inference. Against a matched, one-flag control on the FLIP Meltome thermostability benchmark, the field objective raises Spearman correlation on every trained head of both human splits.The gain on human survives residualizing dipeptide composition under two architecturally different readouts and survives removing the test proteins that overlap the pretraining corpus. No effect survives on the organism-mixed split. At 1.1M parameters, both the Biophysical Transformer and its sequence-only control exceed FLIP's one-hot CNN and untrained-ESM baselines on every split. All results rest on a single pretraining run per arm,and the current design does not separate field content from generic regularization.

biophysics↗
bioRxiv2026

An auditable harness for biomolecular dynamics simulations by AI agents

AI agents now generate biological hypotheses faster than they can be tested. Hypotheses stated at the atomic level can be examined with molecular dynamics (MD) simulations. For new questions without a reference, trust in an agent-run simulation rests on a tool-written process record, not the agent's account. Existing MD agents leave this record to the language model. Here we present MDClaw, a harness whose validating tools and directed acyclic graph (DAG) check stages before execution and record every simulation stage. On MDDataBench, which grades outputs against deposited simulations, four open-weight models with MDClaw passed all three runs on 81-100% of 31 test systems. The DAG complements this outcome check. An ablation without the DAG revealed 11 successful runs that had skipped minimization or equilibration, or simulated a different structure. MDClaw carried questions from human and AI scientists through simulation to trajectories traceable to their inputs and settings.

biophysics↗