p22^phox prevents the oxidation of SERCA2a and stabilizes it in the heart

Sarcoplasmic/endoplasmic reticulum (SR/ER) Ca²⁺ ATPase 2a (SERCA2a) mediates Ca²⁺ reuptake into the SR in cardiomyocytes. The inactivation or downregulation of SERCA2a leads to reduced contractility in the failing heart. Here we show that SERCA2a is regulated by p22^phox, a heterodimeric partner of NADPH oxidases. Endogenous p22^phox was upregulated by pressure overload, but cardiac-specific p22^phox knockout (cKO) in mice exacerbated heart failure, enhanced the downregulation of SERCA2a and increased oxidative stress in the SR. We show that p22^phox interacts with SERCA2a, preventing its oxidation at Cys498 and subsequent degradation by the Smurf1 and Hrd1 E3 ubiquitin ligases. The exacerbation of SERCA2a downregulation and cardiac dysfunction following pressure overload in p22^phox cKO mice was alleviated when these mice were crossed with SERCA2a-C498S knock-in mice, in which the oxidation-susceptible and degradation-promoting cysteine residue is mutated. Future molecular interventions to prevent the oxidation of SERCA2a at Cys498 may prevent its downregulation during heart failure.