Improved mitochondrial function in the hearts of sarcolipin-deficient dystrophin and utrophin double-knockout mice.

Duchenne muscular dystrophy (DMD) is a progressive muscle-wasting disease associated with cardiomyopathy. DMD cardiomyopathy is characterized by abnormal intracellular Ca2+ homeostasis and mitochondrial dysfunction. We used dystrophin and utrophin double-knockout (mdx:utrn-/-) mice in a sarcolipin (SLN) heterozygous-knockout (sln+/-) background to examine the effect of SLN reduction on mitochondrial function in the dystrophic myocardium.

Ser14 phosphorylation of Bcl-xL mediates compensatory cardiac hypertrophy in male mice.

The anti-apoptotic function of Bcl-xL in the heart during ischemia/reperfusion is diminished by K-Ras-Mst1-mediated phosphorylation of Ser14, which allows dissociation of Bcl-xL from Bax and promotes cardiomyocyte death. Here we show that Ser14 phosphorylation of Bcl-xL is also promoted by hemodynamic stress in the heart, through the H-Ras-ERK pathway. Bcl-xL Ser14 phosphorylation-resistant knock-in male mice develop less cardiac hypertrophy and exhibit contractile dysfunction and increased mortality during acute pressure overload.

Deficiency of mitochondrial calcium uniporter abrogates iron overload-induced cardiac dysfunction by reducing ferroptosis.

Iron overload associated cardiac dysfunction remains a significant clinical challenge whose underlying mechanism(s) have yet to be defined. We aim to evaluate the involvement of the mitochondrial Ca uniporter (MCU) in cardiac dysfunction and determine its role in the occurrence of ferroptosis. Iron overload was established in control (MCU) and conditional MCU knockout (MCU) mice.

Molecular Mechanisms of Ferroptosis and Relevance to Cardiovascular Disease.

Ferroptosis has recently been demonstrated to be a novel regulated non-apoptotic cell death characterized by iron-dependence and the accumulation of lipid peroxidation that results in membrane damage. Excessive iron induces ferroptosis by promoting the generation of both soluble and lipid ROS via an iron-dependent Fenton reaction and lipoxygenase (LOX) enzyme activity. Cytosolic glutathione peroxidase 4 (cGPX4) pairing with ferroptosis suppressor protein 1 (FSP1) and mitochondrial glutathione peroxidase 4 (mGPX4) pairing with dihydroorotate dehydrogenase (DHODH) serve as two separate defense systems to detoxify lipid peroxidation in the cytoplasmic as well as the mitochondrial membrane, thereby defending against ferroptosis in cells under normal conditions.