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

Jessica L Braun,Val A Fajardo,Sophie I Hamstra,Holt N Messner

doi:10.14814/phy2.14215

Jessica L Braun, Val A Fajardo + Show 2 more

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https://doi.org/10.14814/phy2.14215

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Journal: Physiological Reports	Publication Date: Aug 1, 2019
Citations: 26	License type: CC BY 4.0

Affiliation: Brock University

Abstract

The sarco/endoplasmic reticulum Ca2+‐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 (TazKD) 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 TazKD LV, a result that correlated with elevated SERCA2a tyrosine nitration. In addition PLN protein was decreased, and its phosphorylation was increased in TazKD 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 TazKD mice. Nonetheless, we demonstrate for the first time that SERCA function is impaired in LVs obtained from young and old TazKD mice likely due to elevated ROS/RNS production. Future studies should determine whether improving SERCA function can improve cardiac contractility and pathology in TazKD mice.

Highlights

The sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) is a P-type ATPase which catalyzes the active transport of Ca2+ ions from the cytoplasm into the sarcoplasmic reticulum (SR) (Misquitta et al, 1999; Periasamy and Huke, 2001; Palmgren and Nissen, 2011)
Similar to previous findings (Acehan et al, 2011), we found a significant interaction of age and genotype on body weight, whereby body weights were similar at 35 months of age, but by 10-12 months, Taz knockdown (TazKD) mice were significantly smaller than WT (Fig. 1A)
While there were no significant differences in left ventricles (LV) wet weight between groups (Fig. 1C), when expressed as a ratio relative to body weight we found a significant interaction indicative of a larger LV:body mass ratio but only in old TazKD mice compared with WT (Fig. 1C)

Summary

Introduction

The sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) is a P-type ATPase which catalyzes the active transport of Ca2+ ions from the cytoplasm into the sarcoplasmic reticulum (SR) (Misquitta et al, 1999; Periasamy and Huke, 2001; Palmgren and Nissen, 2011). Phospholamban (PLN) is a 52 amino acid protein that, in its non-phosphorylated state, binds to and regulates SERCA by decreasing its affinity for Ca2+ (Frank and Kranias, 2000; MacLennan and Kranias, 2003). II (CaMKII), respectively, PLN dissociates from SERCA restoring its affinity for Ca2+ ( MacLennan and Kranias, 2003).

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