Anja Karlstaedt

Oncometabolite d-2-hydroxyglutarate impairs α-ketoglutarate dehydrogenase and contractile function in rodent heart.

Significance We show that the oncometabolite d-2-hydroxyglutarate (D2-HG) affects cardiac function in the isolated working heart by inhibiting α-KGDH, a key regulatory enzyme of cellular energy metabolism. Analyzing metabolic flux rates by using in vitro and ex vivo approaches in combination with integrative mathematical modeling enabled us to identify the mechanisms by which D2-HG perturbs metabolic flux and induces epigenetic modifications in the heart. The results provide knowledge about malignancy-related changes in enzymatic activity and posttranslational modifications in the context of cardiac remodeling. Hematologic malignancies are frequently associated with cardiac pathologies. Mutations of isocitrate dehydrogenase 1 and 2 (IDH1/2) occur in a subset of acute myeloid leukemia patients, causing metabolic and epigenetic derangements. We have now discovered that altered metabolism in leukemic cells has a profound effect on cardiac metabolism. Combining mathematical modeling and in vivo as well as ex vivo studies, we found that increased amounts of the oncometabolite d-2-hydroxyglutarate (D2-HG), produced by IDH2 mutant leukemic cells, cause contractile dysfunction in the heart. This contractile dysfunction is associated with impaired oxidative decarboxylation of α-ketoglutarate, a redirection of Krebs cycle intermediates, and increased ATP citrate lyase (ACL) activity. Increased availability of D2-HG also leads to altered histone methylation and acetylation in the heart. We propose that D2-HG promotes cardiac dysfunction by impairing α-ketoglutarate dehydrogenase and induces histone modifications in an ACL-dependent manner. Collectively, our results highlight the impact of cancer cell metabolism on function and metabolism of the heart.

Impact of membrane phospholipid alterations in Escherichia coli on cellular function and bacterial stress adaptation

Bacteria have evolved multiple strategies to sense and rapidly adapt to challenging and ever-changing environmental conditions. The ability to alter membrane lipid composition, a key component of the cellular envelope, is crucial for bacterial survival and adaptation in response to environmental stress. However, the precise roles played by membrane phospholipids in bacterial physiology and stress adaptation are not fully elucidated. The goal of this study was to define the role of membrane phospholipids in adaptation to stress and maintenance of bacterial cell fitness. By using genetically modified strains in which the membrane phospholipid composition can be systematically manipulated, we show that alterations in major Escherichia coli phospholipids transform these cells globally. We found that alterations in phospholipids impair the cellular envelope structure and function, the ability to form biofilms, and bacterial fitness and cause phospholipid-dependent susceptibility to environmental stresses. This study provides an unprecedented view of the structural, signaling, and metabolic pathways in which bacterial phospholipids participate, allowing the design of new approaches in the investigation of lipid-dependent processes involved in bacterial physiology and adaptation.IMPORTANCE In order to cope with and adapt to a wide range of environmental conditions, bacteria have to sense and quickly respond to fluctuating conditions. In this study, we investigated the effects of systematic and controlled alterations in bacterial phospholipids on cell shape, physiology, and stress adaptation. We provide new evidence that alterations of specific phospholipids in Escherichia coli have detrimental effects on cellular shape, envelope integrity, and cell physiology that impair biofilm formation, cellular envelope remodeling, and adaptability to environmental stresses. These findings hold promise for future antibacterial therapies that target bacterial lipid biosynthesis.

Dynamic Lipid-dependent Modulation of Protein Topology by Post-translational Phosphorylation

Membrane protein topology and folding are governed by structural principles and topogenic signals that are recognized and decoded by the protein insertion and translocation machineries at the time of initial membrane insertion and folding. We previously demonstrated that the lipid environment is also a determinant of initial protein topology, which is dynamically responsive to post-assembly changes in membrane lipid composition. However, the effect on protein topology of post-assembly phosphorylation of amino acids localized within initially cytoplasmically oriented extramembrane domains has never been investigated. Here, we show in a controlled in vitro system that phosphorylation of a membrane protein can trigger a change in topological arrangement. The rate of change occurred on a scale of seconds, comparable with the rates observed upon changes in the protein lipid environment. The rate and extent of topological rearrangement were dependent on the charges of extramembrane domains and the lipid bilayer surface. Using model membranes mimicking the lipid compositions of eukaryotic organelles, we determined that anionic lipids, cholesterol, sphingomyelin, and membrane fluidity play critical roles in these processes. Our results demonstrate how post-translational modifications may influence membrane protein topology in a lipid-dependent manner, both along the organelle trafficking pathway and at their final destination. The results provide further evidence that membrane protein topology is dynamic, integrating for the first time the effect of changes in lipid composition and regulators of cellular processes. The discovery of a new topology regulatory mechanism opens additional avenues for understanding unexplored structure-function relationships and the development of optimized topology prediction tools.

Oncometabolic Tracks in the Heart

The term cancer and the heart is readily associated with the cardiotoxicity of antineoplastic agents, such as anthracyclines or receptor tyrosine kinase inhibitors. This Viewpoint offers a different perspective, drawing attention to the consequences of metabolic dysregulation in cancers for energy substrate metabolism and contractile function of the heart and to common cellular strategies present in cancers and in the failing heart. On the basis of his observations in proliferating ascites tumor cells, Otto Warburg1 proposed that cancer cells derive their energy from the glycolytic breakdown of glucose even in oxygen-rich conditions. Warburg postulated that this metabolic shift, or oncometabolism, arose from dysfunctional mitochondria, and the inability of cancer cells to carry out oxidative phosphorylation. The term oncometabolism refers to an ensemble of metabolic rearrangements that accompany oncogenesis and tumor progression. Recent advances in cancer cell metabolism research have amended Warburg’s seminal findings by showing, for example, that mitochondrial metabolism in cancer cells is not defective. Today’s system-oriented view is that the metabolism of cancer cells is reprogrammed to optimize the flux of glucose and amino acids into biosynthetic pathways supporting proliferation and cell division.2,3 In the context of cancer, metabolic rearrangements are required to enable tumor growth. Similar to cancer cells, cardiac metabolism is remodeled in response to stress, which allows fluxes of intermediary substrates to meet the challenges of energy demand and macromolecule synthesis. There are several lines of evidence for this hypothesis. First, the failing human heart reverts to the metabolic gene program of the fetal heart,4 which causes a shift from predominately utilization of fatty acids to glucose. Second, when stressed by pressure overload, the heart responds with an increase in glucose metabolism, as shown both ex vivo and in vivo.5 In other words, the metabolic remodeling …

Functionally redundant control of cardiac hypertrophic signaling by inositol 1,4,5-trisphosphate receptors

Calcium plays an integral role to many cellular processes including contraction, energy metabolism, gene expression, and cell death. The inositol 1, 4, 5-trisphosphate receptor (IP3R) is a calcium channel expressed in cardiac tissue. There are three IP3R isoforms encoded by separate genes. In the heart, the IP3R-2 isoform is reported to being most predominant with regards to expression levels and functional significance. The functional roles of IP3R-1 and IP3R-3 in the heart are essentially unexplored despite measureable expression levels. Here we show that all three IP3Rs isoforms are expressed in both neonatal and adult rat ventricular cardiomyocytes, and in human heart tissue. The three IP3R proteins are expressed throughout the cardiomyocyte sarcoplasmic reticulum. Using isoform specific siRNA, we found that expression of all three IP3R isoforms are required for hypertrophic signaling downstream of endothelin-1 stimulation. Mechanistically, IP3Rs specifically contribute to activation of the hypertrophic program by mediating the positive inotropic effects of endothelin-1 and leading to downstream activation of nuclear factor of activated T-cells. Our findings highlight previously unidentified functions for IP3R isoforms in the heart with specific implications for hypertrophic signaling in animal models and in human disease.

Actionable Metabolic Pathways in Heart Failure and Cancer—Lessons From Cancer Cell Metabolism

Recent advances in cancer cell metabolism provide unprecedented opportunities for a new understanding of heart metabolism and may offer new approaches for the treatment of heart failure. Key questions driving the cancer field to understand how tumor cells reprogram metabolism and to benefit tumorigenesis are also applicable to the heart. Recent experimental and conceptual advances in cancer cell metabolism provide the cardiovascular field with the unique opportunity to target metabolism. This review compares cancer cell metabolism and cardiac metabolism with an emphasis on strategies of cellular adaptation, and how to exploit metabolic changes for therapeutic benefit.

Letter by Karlstaedt and Taegtmeyer Regarding Article, “Loss of Adult Cardiac Myocyte GSK-3 Leads to Mitotic Catastrophe Resulting in Fatal Dilated Cardiomyopathy”

We have read with interest the article by Zhou et al.1 The authors demonstrated that in cardiomyocytes, conditional deletion of glycogen synthase kinase-3 (GSK-3) isoforms A and B leads to development of severe dilated cardiomyopathy. Zhou et al1 also report that GSK-3 suppresses cell cycle induction and that the subsequent loss of cardiac myocytes leads to impaired contractile function, development of dilated cardiomyopathy, and death. These are exciting findings, which are in agreement with …