SERCA2a tyrosine nitration coincides with impairments in maximal SERCA activity in left ventricles from tafazzin‐deficient mice

Abstract

The sarco/endoplasmic reticulum Ca 2+ ‐ATPase (SERCA) is imperative for normal cardiac function regulating both muscle relaxation and contractility. SERCA2a is the predominant isoform in cardiac muscles and is inhibited by phospholamban (PLN). Under conditions of oxidative stress, SERCA2a may also be impaired by tyrosine nitration. Tafazzin (Taz) is a mitochondrial‐specific transacylase that regulates mature cardiolipin (CL) formation, and its absence leads to mitochondrial dysfunction and excessive production of reactive oxygen/nitrogen species (ROS/RNS). In the present study, we examined SERCA function, SERCA2a tyrosine nitration, and PLN expression/phosphorylation in left ventricles (LV) obtained from young (3‐5 months) and old (10‐12 months) wild‐type (WT) and Taz knockdown (Taz KD ) male mice. These mice are a mouse model for Barth syndrome, which is characterized by mitochondrial dysfunction, excessive ROS/RNS production, and dilated cardiomyopathy (DCM). Here, we show that maximal SERCA activity was impaired in both young and old Taz KD LV, a result that correlated with elevated SERCA2a tyrosine nitration. In addition PLN protein was decreased, and its phosphorylation was increased in Taz KD LV compared with control, which suggests that PLN may not contribute to the impairments in SERCA function. These changes in expression and phosphorylation of PLN may be an adaptive response aimed to improve SERCA function in Taz KD mice. Nonetheless, we demonstrate for the first time that SERCA function is impaired in LVs obtained from young and old Taz KD mice likely due to elevated ROS/RNS production. Future studies should determine whether improving SERCA function can improve cardiac contractility and pathology in Taz KD mice.

The Hypoxia Tolerance of the Goldfish (Carassius auratus) Heart: The NOS/NO System and Beyond

“…When phosphorylated, PLN dissociates from SERCA2a, thus restoring its affinity for Ca 2+ [ 79 ]. SERCA2a pumps are susceptible to oxidative and nitrosative modifications, as they contain vulnerable cysteine and tyrosine residues (see, for reference, [ 68 , 80 ]). The nitrotyrosine modification of SERCA2a has been observed in several pathophysiological conditions [ 73 , 81 ], and nitrated SERCA2a has been recently considered as a cardiac marker of nitrative stress [ 68 ].…”

Neuronatin regulates whole‐body metabolism: is thermogenesis involved?

“…Western blotting and co-immunoprecipitation protocols were performed as previously described using 4%-15% TGX precast gels (Bio-Rad Laboratories) and PVDF membranes. 50,[60][61][62] Primary antibodies for NNAT were obtained from ProteinTech (26905-1-AP), whereas SERCA1a (MA3-912) and SERCA2a (MA3-919) were obtained from ThermoFisher…”

“…Mice were fed a standard chow diet and housed under 12 h light:dark periods; and all animal protocols were approved by the Brock University Animal Care Committee. Western blotting and co‐immunoprecipitation protocols were performed as previously described using 4%‐15% TGX precast gels (Bio‐Rad Laboratories) and PVDF membranes 50,60–62 . Primary antibodies for NNAT were obtained from ProteinTech (26905‐1‐AP), whereas SERCA1a (MA3‐912) and SERCA2a (MA3‐919) were obtained from ThermoFisher…”

Unbalance Between Sarcoplasmic Reticulum Ca2 + Uptake and Release: A First Step Toward Ca2 + Triggered Arrhythmias and Cardiac Damage

“…The SERCA2a residue mainly involved in this reaction is the reactive thiol group Cys 674 (Adachi et al, 2004). However, an exacerbated increase of ONOO − nitrosylates the hydroxyl groups of SERCA2a, producing impairment of cardiac relaxation (Braun et al, 2019).…”