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High resolution structural evidence suggests the Sarcoplasmic Reticulum forms microdomains with acidic stores (lysosomes) in the heart

Aston, Daniel; Capel, Rebecca A.; Ford, Kerrie L.; Christian, Helen C.; Mirams, Gary R.; Rog-Zielinska, Eva A.; Kohl, Peter; Galione, Antony; Burton, Rebecca A.B.; Terrar, Derek A.

Authors

Daniel Aston

Rebecca A. Capel

Kerrie L. Ford

Helen C. Christian

Eva A. Rog-Zielinska

Peter Kohl

Antony Galione

Rebecca A.B. Burton

Derek A. Terrar



Abstract

Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) stimulates calcium release from acidic stores such as lysosomes and is a highly potent calcium-mobilising second messenger. NAADP plays an important role in calcium signalling in the heart under basal conditions and following β-adrenergic stress. Nevertheless, the spatial interaction of acidic stores with other parts of the calcium signalling apparatus in cardiac myocytes is unknown. We present evidence that lysosomes are intimately associated with the sarcoplasmic reticulum (SR) in ventricular myocytes; a median separation of 20 nm in 2D electron microscopy and 3.3 nm in 3D electron tomography indicates a genuine signalling microdomain between these organelles. Fourier analysis of immunolabelled lysosomes suggests a sarcomeric pattern (dominant wavelength 1.80 μm). Furthermore, we show that lysosomes form close associations with mitochondria (median separation 6.2 nm in 3D studies) which may provide a basis for the recently-discovered role of NAADP in reperfusion-induced cell death. The trigger hypothesis for NAADP action proposes that calcium release from acidic stores subsequently acts to enhance calcium release from the SR. This work provides structural evidence in cardiac myocytes to indicate the formation of microdomains between acidic and SR calcium stores, supporting emerging interpretations of NAADP physiology and pharmacology in heart.

Journal Article Type Article
Publication Date Jan 17, 2017
Journal Scientific Reports
Print ISSN 2045-2322
Electronic ISSN 2045-2322
Publisher Nature Publishing Group
Peer Reviewed Peer Reviewed
Volume 7
Article Number 40620
APA6 Citation Aston, D., Capel, R. A., Ford, K. L., Christian, H. C., Mirams, G. R., Rog-Zielinska, E. A., …Terrar, D. A. (2017). High resolution structural evidence suggests the Sarcoplasmic Reticulum forms microdomains with acidic stores (lysosomes) in the heart. Scientific Reports, 7, https://doi.org/10.1038/srep40620
DOI https://doi.org/10.1038/srep40620
Publisher URL https://www.nature.com/articles/srep40620
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0





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