SERCA2 phosphorylation at serine 663 is a key regulator of Ca2+ homeostasis in heart diseases

Fabrice Gonnot, Laura Boulogne, Camille Brun, Maya Dia, Yves Gouriou, Gabriel Bidaux, Christophe Chouabe, Claire Crola Da Silva, Sylvie Ducreux, Bruno Pillot, Andrea Kaczmarczyk, Christelle Leon, Stephanie Chanon, Coralie Perret, Franck Sciandra, Tanushri Dargar, Vincent Gache, Fadi Farhat, Laurent Sebbag, Thomas Bochaton, Helene Thibault, Michel Ovize, Melanie Paillard and Ludovic Gomez ()
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Fabrice Gonnot: Université Claude Bernard Lyon-1, INSA-Lyon, Univ-Lyon
Laura Boulogne: Université Claude Bernard Lyon-1, INSA-Lyon, Univ-Lyon
Camille Brun: Université Claude Bernard Lyon-1, INSA-Lyon, Univ-Lyon
Maya Dia: Université Claude Bernard Lyon-1, INSA-Lyon, Univ-Lyon
Yves Gouriou: Université Claude Bernard Lyon-1, INSA-Lyon, Univ-Lyon
Gabriel Bidaux: Université Claude Bernard Lyon-1, INSA-Lyon, Univ-Lyon
Christophe Chouabe: Université Claude Bernard Lyon-1, INSA-Lyon, Univ-Lyon
Claire Crola Da Silva: Université Claude Bernard Lyon-1, INSA-Lyon, Univ-Lyon
Sylvie Ducreux: Université Claude Bernard Lyon-1, INSA-Lyon, Univ-Lyon
Bruno Pillot: Université Claude Bernard Lyon-1, INSA-Lyon, Univ-Lyon
Andrea Kaczmarczyk: Université Claude Bernard Lyon-1, INSA-Lyon, Univ-Lyon
Christelle Leon: Université Claude Bernard Lyon-1, INSA-Lyon, Univ-Lyon
Stephanie Chanon: Université Claude Bernard Lyon-1, INSA-Lyon, Univ-Lyon, Functional Lipidomic Plateform
Coralie Perret: Université Claude Bernard Lyon-1, INSA-Lyon, Univ-Lyon
Franck Sciandra: Université Claude Bernard Lyon-1, INSA-Lyon, Univ-Lyon
Tanushri Dargar: Université Claude Bernard Lyon 1
Vincent Gache: Université Claude Bernard Lyon 1
Fadi Farhat: Université Claude Bernard Lyon-1, INSA-Lyon, Univ-Lyon
Laurent Sebbag: Université Claude Bernard Lyon-1, INSA-Lyon, Univ-Lyon
Thomas Bochaton: Université Claude Bernard Lyon-1, INSA-Lyon, Univ-Lyon
Helene Thibault: Université Claude Bernard Lyon-1, INSA-Lyon, Univ-Lyon
Michel Ovize: Université Claude Bernard Lyon-1, INSA-Lyon, Univ-Lyon
Melanie Paillard: Université Claude Bernard Lyon-1, INSA-Lyon, Univ-Lyon
Ludovic Gomez: Université Claude Bernard Lyon-1, INSA-Lyon, Univ-Lyon

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract Despite advances in cardioprotection, new therapeutic strategies capable of preventing ischemia-reperfusion injury of patients are still needed. Here, we discover that sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA2) phosphorylation at serine 663 is a clinical and pathophysiological event of cardiac function. Indeed, the phosphorylation level of SERCA2 at serine 663 is increased in ischemic hearts of patients and mouse. Analyses on different human cell lines indicate that preventing serine 663 phosphorylation significantly increases SERCA2 activity and protects against cell death, by counteracting cytosolic and mitochondrial Ca2+ overload. By identifying the phosphorylation level of SERCA2 at serine 663 as an essential regulator of SERCA2 activity, Ca2+ homeostasis and infarct size, these data contribute to a more comprehensive understanding of the excitation/contraction coupling of cardiomyocytes and establish the pathophysiological role and the therapeutic potential of SERCA2 modulation in acute myocardial infarction, based on the hotspot phosphorylation level of SERCA2 at serine 663 residue.

Date: 2023
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DOI: 10.1038/s41467-023-39027-x

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