Lysosomal signalling pathways influence heart rhythm, and regulate atrial function


Capel RA, Akerman E, Rog-Zielinska E, Winbo A, Aston D, Mu-u-min RBA, Read MJ, Bose SJ, Swietach P, Wang J, Corbett AD, Koschinski A, Montgomery JM, Falter F, Calamaio S, Melgari D, Prevostini R, Rivolta I, Ayagama T, Jenkin I, Simon JN, Fakuade FE, Pronto J, Sharma P, Song Q, Booth MJ, Platt FM, Lei M, Hester S, Fischer R, Voigt N, Schotten U, Verheule S, Galione A, Keller M, Bracher F, Zaccolo M, Terrar DA, Burton RAB




bioRxiv 2024.06.10.597905.


In the heart, endogenous nicotinic acid adenine dinucleotide phosphate (NAADP) triggers lysosomal calcium release to augment sarcoplasmic reticulum (SR) calcium sequestration, producing larger calcium transients. However, the role of lysosomal calcium signals in pacemaker activity, a distinct calcium-operated function of the sino-atrial node (SAN) or atria, a distinct calcium-operated function, has not been investigated. Pharmacological or genetic ablation of the NAADP pathway inhibits spontaneous beating rate response to beta-adrenergic stimulation in intact SAN. We found intracellular signalling microdomains between lysosomes and neighbouring SR or mitochondria in mouse, rabbit, goat, and human atrial tissue. The spatial relationship between lysosomes and other calcium-handling organelles are altered in goat and human atrial fibrillation. Furthermore, we demonstrate atrial myocytes produce 3′-5′-cyclic adenosine monophosphate in response to lysosomal signalling, adding a novel trigger for cyclic nucleotide signalling. Our findings support the hypothesis that lysosomal calcium signaling directly increases cardiomyocyte cAMP and modulates pacemaker activity.Competing Interest StatementThe authors have declared no competing interest.