Scientists have discovered that lysosomes, structures traditionally viewed as the cell's recycling centres, also play a role in regulating the heart's natural rhythm.
Researchers at the University of Liverpool and University of Oxford, working with national and international collaborators, found that lysosomes act as signalling centres in heart cells, helping the heart's natural pacemaker respond when the heart needs to beat faster.
The findings, published in Cardiovascular Research Journal, provide fresh insight into the biological processes involved in regulating heart rhythm and could help inform future studies into conditions such as atrial fibrillation, a common heart rhythm disorder.
Previous studies had shown that lysosomes can influence calcium signalling in heart cells. However, until now, their role in controlling the heart's pacemaker and heart rate had not been investigated.
To explore this, the researchers combined animal studies with experiments using laboratory-grown human heart cells and human cardiac tissue. Findings from mice, guinea pigs, rats and goats helped them investigate how lysosomal signalling contributes to heart function in healthy and diseased tissue.
The researchers found that:
- Lysosomes play an important role in regulating heart rate.
- They communicate through a previously unidentified signalling pathway involving cAMP, one of the key messenger molecules involved in accelerating heart rate.
- Components of this pathway appear to be altered in atrial fibrillation.
Associate Professor Rebecca-Ann Burton, from the Department of Pharmacology and Therapeutics at the University of Liverpool and senior corresponding author of the study, said: "These findings reveal a previously unrecognised link between lysosomal calcium signalling and the pathways that regulate the heart's natural pacemaker.
"This is the first study to show that lysosomal calcium signalling can trigger the production of cAMP in heart cells, rather than simply strengthening existing calcium signals. It is also the first to demonstrate a specific role for this pathway in cardiac pacemaking.
"Together, these findings expand our understanding of how heart cells coordinate signalling and may provide new avenues for investigating heart rhythm disorders."
The study showed that signals originating from lysosomes help the heart's natural pacemaker respond to stimulation that normally increases heart rate. Researchers also found that lysosomes can increase levels of cAMP, one of the key messenger molecules involved in accelerating heart rate.
The team identified two proteins, CaMKII and AC1, as likely components of this pathway. AC1 was located close to lysosomes within heart cells, suggesting that lysosome-derived calcium signals may be rapidly relayed to the cellular systems that help control heart rhythm.
The researchers also investigated the role of lysosomes in atrial fibrillation. They found that lysosomes were larger in both animal models and human tissue samples and exhibited altered spatial relationships with other cellular structures compared with sinus rhythm control tissue. The team also identified changes in proteins linked to lysosomal function and autophagy, the cellular process responsible for breaking down and recycling damaged components.
Clinician scientist, Professor Niels Voigt from the Medical Faculty Mannheim at Heidelberg University and also author on this study said: "Atrial fibrillation is the most common cardiac arrhythmia, and targeting lysosomal signalling may open an entirely new avenue for developing treatments for this common condition."
Professor Antony Galione, Department of Pharmacology, University of Oxford, and an author on the study, added: "This study identifies yet another specific role for lysosomal calcium release underscoring how these small organelles can provide highly localized calcium signals to regulate key cellular processes in a selective way"
Together, these findings suggest that atrial fibrillation is associated with structural remodelling within atrial heart muscle cells, including changes in intracellular signalling domains and organelle organisation. Further studies are needed to determine how these alterations contribute to the development or progression of the disease.
The work has been funded by the Royal Society and Wellcome Trust.
The paper, 'Lysosomal signaling pathways influence heart rhythm, and regulate atrial function', was published in Cardiovascular Journal (DOI:10.1093/cvr/cvag207).
