Lethal Arg9Cys phospholamban mutation increases the mitochondrial fission protein (Drp-1) activity

An Arg9 to Cys point mutation in phospholamban (PLN) is the leading cause of dilated cardiomyopathy (DCM) in both humans and in transgenic mice (TgPLNR9C mice). An earlier proteomics analysis of these mice showed that many proteins classified under the Gene Ontology (GO) term functional categories of 'reduced mitochondrial function' and 'disruption of energy production' were significantly reduced. Here, we show that COX activity measured in mitochondria isolated from ventricles of these mice was significantly reduced compared to wild type. At the same time, electron microscopy showed extensive mitochondrial damage. Since PLN is a regulator of the sarco/endo plasmic reticulum Ca2+-ATPase (SERCA2a), we examined the translocation of stromal interaction molecule 1 (STIM1) to speculate Ca2+ store in SR. STIM1 formed punctae in R9C cells, indicating a reduction in the size of the Ca2+ store. This change in the Ca2+ store was associated with ER stress and changes in the phosphorylation status of several proteins...