Activation of the integrated stress response rewires cardiac metabolism in Barth syndrome.

Barth Syndrome (BTHS) is an inherited cardiomyopathy caused by defects in the mitochondrial transacylase TAFAZZIN (Taz), required for the synthesis of the phospholipid cardiolipin. BTHS is characterized by heart failure, increased propensity for arrhythmias and a blunted inotropic reserve. Defects in Ca2+-induced Krebs cycle activation contribute to these functional defects, but despite oxidation of pyridine nucleotides, no oxidative stress developed in the heart. Here, we investigated how retrograde signaling pathways orchestrate metabolic rewiring to compensate for mitochondrial defects. In mice with an inducible knockdown (KD) of TAFAZZIN, and in induced pluripotent stem cell-derived cardiac myocytes, mitochondrial uptake and oxidation of fatty acids was strongly decreased, while glucose uptake was increased. Unbiased transcriptomic analyses revealed that the activation of the eIF2α/ATF4 axis of the integrated stress response upregulates one-carbon metabolism, which diverts glycolytic intermediates towards the biosynthesis of serine and fuels the biosynthesis of glutathione. In addition, strong upregulation of the glutamate/cystine antiporter xCT increases cardiac cystine import required for glutathione synthesis. Increased glutamate uptake facilitates anaplerotic replenishment of the Krebs cycle, sustaining energy production and antioxidative pathways. These data indicate that ATF4-driven rewiring of metabolism compensates for defects in mitochondrial uptake of fatty acids to sustain energy production and antioxidation.

Metabolic Alterations Caused by Defective Cardiolipin Remodeling in Inherited Cardiomyopathies.

The heart is the most energy-consuming organ in the human body. In heart failure, the homeostasis of energy supply and demand is endangered by an increase in cardiomyocyte workload, or by an insufficiency in energy-providing processes. Energy metabolism is directly associated with mitochondrial redox homeostasis. The production of toxic reactive oxygen species (ROS) may overwhelm mitochondrial and cellular ROS defense mechanisms in case of heart failure. Mitochondria are essential cell organelles and provide 95% of the required energy in the heart. Metabolic remodeling, changes in mitochondrial structure or function, and alterations in mitochondrial calcium signaling diminish mitochondrial energy provision in many forms of cardiomyopathy. The mitochondrial respiratory chain creates a proton gradient across the inner mitochondrial membrane, which couples respiration with oxidative phosphorylation and the preservation of energy in the chemical bonds of ATP. Akin to other mitochondrial enzymes, the respiratory chain is integrated into the inner mitochondrial membrane. The tight association with the mitochondrial phospholipid cardiolipin (CL) ensures its structural integrity and coordinates enzymatic activity. This review focuses on how changes in mitochondrial CL may be associated with heart failure. Dysfunctional CL has been found in diabetic cardiomyopathy, ischemia reperfusion injury and the aging heart. Barth syndrome (BTHS) is caused by an inherited defect in the biosynthesis of cardiolipin. Moreover, a dysfunctional CL pool causes other types of rare inherited cardiomyopathies, such as Sengers syndrome and Dilated Cardiomyopathy with Ataxia (DCMA). Here we review the impact of cardiolipin deficiency on mitochondrial functions in cellular and animal models. We describe the molecular mechanisms concerning mitochondrial dysfunction as an incitement of cardiomyopathy and discuss potential therapeutic strategies.

Chromatographic property classification of narrowly distributed ZnS quantum dots.

Although optimized synthesis methods for nanoparticles (NPs) on small scale can lead to narrow particle size distributions (PSDs) and thus defined optical properties, in particular during scale-up, an additional classification step must be applied to adjust the particle properties according to the needs of the later application. NP chromatography is a promising separation method, which can be potentially transferred to preparative and industrial scale. Herein, we demonstrate that remarkable classification of ZnS quantum dots (QDs) with respect to the fundamental band gap energy is achieved by chromatography although the PSD of the feed material is already very narrow (1.5-3.0 nm). We investigated the interactions of ZnS QDs with stationary and mobile phase materials in order to select a proper material couple so that irreversible NP adhesion, agglomeration, decomposition or dissolution of the ZnS QDs during the chromatographic experiments are avoided and highly reproducible chromatograms are obtained. Using a fraction collector, the already narrowly size distributed feed material was separated into coarse and fine fractions with distinct band gap energies. For characterization of the chromatographic fractionation, quantities known from particle technology, i.e. separation efficiency, cut size and yield, were adapted to the band gap energy distributions accessible from UV/Vis spectroscopy. The optimization of process conditions (flow rate, temperature, switching time of the fraction collector) allows fine-tuning of the property classification and therefore of the optical properties within the narrow distribution of the ZnS QDs. Our study shows the strength and high potential of chromatography for preparative and continuous separation of NPs even in case of narrow size-distributed sub-10 nm semiconductor QDs.