Lysosomal signaling pathways influence heart rhythm, and regulate atrial function
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.
Authors
- Serena Calamaio (ORCID: https://orcid.org/0000-0002-6616-1005)
- Ifan Jenkin (ORCID: https://orcid.org/0000-0003-3690-0847)
- Jillian N. Simon (ORCID: https://orcid.org/0000-0001-8140-7782)
- Julius Ryan D. Pronto (ORCID: https://orcid.org/0000-0003-3556-5637)
- Román Fischer (ORCID: https://orcid.org/0000-0002-9715-5951)
- Parveen Sharma (ORCID: https://orcid.org/0000-0002-5534-2417)
- Pawel Swietach (ORCID: https://orcid.org/0000-0002-9945-9473)
- Niels Voigt (ORCID: https://orcid.org/0000-0001-8230-2341)
- Dario Melgari (ORCID: https://orcid.org/0000-0002-0563-8041)
- Marie Held (ORCID: https://orcid.org/0000-0003-0118-5898)
- Alexander D. Corbett (ORCID: https://orcid.org/0000-0003-1645-5475)
- Florian Falter (ORCID: https://orcid.org/0000-0002-7870-1136)
- Manuela Zaccolo (ORCID: https://orcid.org/0000-0002-0934-3662)
- Franz Bracher (ORCID: https://orcid.org/0000-0003-0009-8629)
- Ulrich Schotten (ORCID: https://orcid.org/0000-0003-1532-3315)
- Andreas Koschinski (ORCID: https://orcid.org/0000-0003-1876-3279)
- Derek A. Terrar (ORCID: https://orcid.org/0000-0001-9408-6594)
- Sander Verheule (ORCID: https://orcid.org/0000-0001-5196-5425)
- Ilaria Rivolta (ORCID: https://orcid.org/0000-0002-7411-9069)
- Rachele Prevostini (ORCID: https://orcid.org/0009-0005-8238-4443)
- Annika Winbo (ORCID: https://orcid.org/0000-0002-9323-3166)
- Thamali Ayagama (ORCID: https://orcid.org/0000-0003-4432-5491)
- Eva A. Rog‐Zielinska (ORCID: https://orcid.org/0000-0002-3295-4728)
- Martin J. Booth (ORCID: https://orcid.org/0000-0002-9525-8981)
- Rebecca A.B. Burton (ORCID: https://orcid.org/0000-0002-0904-3862)
- Samuel J. Bose (ORCID: https://orcid.org/0000-0003-2922-3075)
- Qianqian Song (ORCID: https://orcid.org/0000-0002-4455-5302)
- Ming Lei (ORCID: https://orcid.org/0000-0002-0928-341X)
- Matthew J. Read
- Razik Bin Abdul Mu-U-Min
- Aiswarya Dev
- Svenja Hester
- Marco Keller
- Charlotte Melia
- Rebecca A B Burton
- Emily Akerman
- Antony Galione (ORCID: https://orcid.org/0000-0002-4132-7646)
- Thomas Waring
- Frances M Platt
- Funsho E Fakuade
- Jingyu Wang
- Daniel Aston
Institutions
- University of Liverpool (GB)
- University of Auckland (NZ)
- University of Freiburg (DE)
- University of Exeter (GB)
- Maastricht University (NL)
- University of Oxford (GB)
- Liverpool Heart and Chest Hospital (GB)
- IRCCS Policlinico San Donato (IT)
- Papworth Hospital NHS Foundation Trust (GB)
- Universitätsmedizin Göttingen (DE)
- German Centre for Cardiovascular Research (DE)
- Science Oxford (GB)
- Institute of Pharmacology (CZ)
- Liverpool John Moores University (GB)
- University of Milano-Bicocca (IT)
- University of Göttingen (DE)
- Ludwig-Maximilians-Universität München (DE)
- Temple University (US)
Publication Details
- Journal
- Cardiovascular Research
- Published
- 2026-09-19
- DOI
- https://doi.org/10.1093/cvr/cvag207
- Primary Topic
- Calcium signaling and nucleotide metabolism
- Type
- article
- Field-Weighted Citation Impact
- 0.00