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

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.

Far-red and sensitive sensor for monitoring real time H2O2 dynamics with subcellular resolution and in multi-parametric imaging applications.

“…4D ]. It is widely accepted that oxidative stress perturbs key Ca 2+ transporters like ryanodine receptors (Sarcoplasmic reticulum Ca 2+ leak) 46 , L-type calcium channels (ICaL, inward Ca 2+ current) 47 , and sarcoplasmic reticulum calcium ATPase pumps (SERCA, decreased Ca 2+ reuptake) 48 – 50 . Functional influence of these perturbations can manifest as changes in specific CaT phenotypes such as baseline Ca 2+ level, CaT amplitude, Time-to-Peak (TtP, on-kinetics), and Calcium Transient Duration 90% (CaTD90, completion of 90% of one CaT period).…”

Myocardial SERCA2 Protects Against Cardiac Damage and Dysfunction Caused by Inhaled Bromine

“…Cardiomyocytes of the cardiac-specific SERCA KO mice have a significantly altered phenotype, but ultrastructural damage has not been reported ( Andersson et al, 2009 ). SERCA2 inactivation is central to cardiac cell death and injury caused by ischemia reperfusion and myocardial infarction ( Gonnot et al, 2023 ). The ensuing mitochondrial fission fusion changes and subsequent damage are also critical in the cytosolic overload induced by Br 2 inhalation and/or SERCA2 inactivation ( Ahmad et al, 2019 ; Hernandez-Resendiz et al, 2023 ; Murphy and Liu 2023 ).…”

Calcium signaling from sarcoplasmic reticulum and mitochondria contact sites in acute myocardial infarction

“…Elevated phosphorylation at this site is evident in ischemic hearts of both patients and preclinical models. Inhibiting serine 663 phosphorylation, through a CRISPR/Cas9-mediated genome editing strategy allowed to generate a human cell line expressing a phosphoresistant SERCA2 mutant (SERCA2 S663A ), enhances SERCA2 activity, offering protection against cell death by mitigating cytosolic and mitochondrial Ca 2+ overload [ 96 ]. The above-mentioned necrosis and apoptosis are only two of the plethora of cell death mechanisms by which cells die after stressors [ 97 ] and in which Ca 2+ and inflammation are crucial factors.…”