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

• Published in: Physiological reports Vol. 7; no. 16; pp. e14215 - n/a
• Main Authors: Braun, Jessica L., Hamstra, Sophie I., Messner, Holt N., Fajardo, Val A.
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.08.2019; John Wiley and Sons Inc; Wiley
• Subjects: Adenosine triphosphatase; Animals; Barth Syndrome - metabolism; Ca2+ regulation; Ca2+-transporting ATPase; Calcium (reticular); Calcium-Binding Proteins - metabolism; Cardiac Muscle; Cardiolipin; Cardiomyopathy; Dilated cardiomyopathy; Disease Models, Animal; Endocrine and Metabolic Conditons, Disorders and Treatments; Endoplasmic reticulum; Gene Knockdown Techniques; Heart; Heart Ventricles - metabolism; Kinases; Laboratories; Male; Mice; Mitochondria; Muscle contraction; Muscle Contraction and Relaxation; Nitration; Original Research; Oxidative stress; Oxidative Stress - physiology; Phospholamban; Phosphorylation; Proteins; Reactive nitrogen species; Reactive oxygen species; Sarcoplasmic Reticulum Calcium-Transporting ATPases - metabolism; Signalling Pathways; Software; Transcription Factors - deficiency; Tyrosine; Tyrosine - metabolism; Ca2+ regulation; phospholamban; dilated cardiomyopathy
• ISSN: 2051-817X
• DOI: 10.14814/phy2.14215

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. This study characterizes SERCA function in left ventricles from tafazzin‐deficient mice. The present findings show that maximal SERCA function is impaired likely due to enhanced tyrosine nitration.