Lysosomal signaling pathways influence heart rhythm, and regulate atrial function

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ID: 329174
2026
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Abstract
AIMS: In the heart, endogenous nicotinic acid adenine dinucleotide phosphate (NAADP) triggers lysosomal calcium (Ca2+) release to augment sarcoplasmic reticulum (SR) Ca2+ sequestration, producing larger Ca2+ transients. However, the role of lysosomal Ca2+ signals in pacemaker activity, a distinct Ca2+-operated function of the sinoatrial node (SAN), or in the atrial myocardium has not been investigated. METHODS AND RESULTS: Pharmacological or genetic ablation of the NAADP pathway inhibits the spontaneous beating rate response to β-adrenergic stimulation in intact SAN. We found intracellular signaling microdomains between lysosomes and neighboring SR or mitochondria in mouse, and goat tissue. The spatial relationship between lysosomes and other Ca2+-handling organelles are altered in goat atrial fibrillation. Furthermore, we demonstrate atrial myocytes produce 3'-5'-cyclic adenosine monophosphate (cAMP) in response to lysosomal signaling, adding a novel trigger for cyclic nucleotide signaling. CONCLUSIONS: Our findings support the hypothesis that lysosomal Ca2+ signaling contributes to regulation of cardiomyocyte cAMP levels and pacemaker activity.
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Authors Emily Akerman, Rebecca A.B. Burton, Eva A. Rog‐Zielinska, Annika Winbo, Daniel Aston, Florian Falter, Razik Bin Abdul Mu-U-Min, Matthew J. Read, Samuel J. Bose, Pawel Swietach, Jingyu Wang, Alexander D. Corbett, Andreas Koschinski, Serena Calamaio, Dario Melgari, Rachele Prevostini, Ilaria Rivolta, Thamali Ayagama, Ifan Jenkin, Jillian N. Simon, Funsho E Fakuade, Julius Ryan D. Pronto, Parveen Sharma, Charlotte Melia, Qianqian Song, Martin J. Booth, Frances M Platt, Ming Lei, Svenja Hester, Román Fischer, Niels Voigt, Ulrich Schotten, Sander Verheule, Aiswarya Dev, Marie Held, Thomas Waring, Antony Galione, Marco Keller, Franz Bracher, Manuela Zaccolo, Derek A. Terrar, Rebecca A.B. Burton
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Journal cardiovascular research
Year 2026
DOI
10.1093/cvr/cvag207
URL
https://doi.org/10.1093/cvr/cvag207
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