bims-carmet 2022-01-23 papers

bims-carmet

Biomed News

on Cardiac metabolism

Issue of 2022–01–23
ten papers selected by
Mikky Atsér, University of British Columbia

Deranged Myocardial Fatty Acid Metabolism in Heart Failure.
Modelling Metabolic Shifts during Cardiomyocyte Differentiation, Iron Deficiency and Transferrin Rescue Using Human Pluripotent Stem Cells.
NAD supplementation improves mitochondrial performance of cardiolipin mutants.
Effect of l-carnitine and mildronate on the mitochondrial metabolism of heart and bacterial composition of the gut microbiome in ageing mice.
Melatonin Attenuates Ischemia/Reperfusion-Induced Oxidative Stress by Activating Mitochondrial Fusion in Cardiomyocytes.
Inhibition of fatty acid translocase (FAT/CD36) palmitoylation enhances hepatic fatty acid β-oxidation by increasing its localization to mitochondria and interaction with long-chain acyl-CoA synthetase 1.
Metabolic and Physiological Regulation of Aspartic Acid-Mediated Enhancement of Heat Stress Tolerance in Perennial Ryegrass.
MDH2 produced OAA is a metabolic switch rewiring the fuelling of respiratory chain and TCA cycle.
The Role of Mitochondrial DNA Mutations in Cardiovascular Diseases.
The Oxidative Balance Orchestrates the Main Keystones of the Functional Activity of Cardiomyocytes.

Int J Mol Sci. 2022 Jan 17. pii: 996. [Epub ahead of print]23(2):

Deranged Myocardial Fatty Acid Metabolism in Heart Failure.

Tsunehisa Yamamoto, Motoaki Sano.

  The heart requires fatty acids to maintain its activity. Various mechanisms regulate myocardial fatty acid metabolism, such as energy production using fatty acids as fuel, for which it is known that coordinated control of fatty acid uptake, β-oxidation, and mitochondrial oxidative phosphorylation steps are important for efficient adenosine triphosphate (ATP) production without unwanted side effects. The fatty acids taken up by cardiomyocytes are not only used as substrates for energy production but also for the synthesis of triglycerides and the replacement reaction of fatty acid chains in cell membrane phospholipids. Alterations in fatty acid metabolism affect the structure and function of the heart. Recently, breakthrough studies have focused on the key transcription factors that regulate fatty acid metabolism in cardiomyocytes and the signaling systems that modify their functions. In this article, we reviewed the latest research on the role of fatty acid metabolism in the pathogenesis of heart failure and provide an outlook on future challenges.

Keywords:  ER stress; ERR; MUFA; PPAR; SCD1; SFA; SIRT1; membrane fatty acid composition; triacylglyceride; β-oxidation

DOI:  https://doi.org/10.3390/ijms23020996
Metabolites. 2021 Dec 22. pii: 9. [Epub ahead of print]12(1):

Modelling Metabolic Shifts during Cardiomyocyte Differentiation, Iron Deficiency and Transferrin Rescue Using Human Pluripotent Stem Cells.

Benjamin B Johnson, Johannes Reinhold, Terri L Holmes, Jamie A Moore, Verity Cowell, Andreia S Bernardo, Stuart A Rushworth, Vassilios Vassiliou, James G W Smith.

  Cardiomyocytes rely on specialised metabolism to meet the high energy demand of the heart. During heart development, metabolism matures and shifts from the predominant utilisation of glycolysis and glutamine oxidation towards lactate and fatty acid oxidation. Iron deficiency (ID) leads to cellular metabolism perturbations. However, the exact alterations in substrate metabolism during ID are poorly defined. Using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM), the present study investigated changes in major metabolic substrate utilisation in the context of ID or upon transferrin rescue. Typically, during hiPSC-CM differentiation, the greatest increase in total metabolic output and rate was seen in fatty acid metabolism. When ID was induced, hiPSC-CMs displayed increased reliance on glycolytic metabolism, and six TCA cycle, five amino acid, and four fatty acid substrates were significantly impaired. Transferrin rescue was able to improve TCA cycle substrate metabolism, but the amino acid and fatty acid metabolism remained perturbed. Replenishing iron stores partially reverses the adverse metabolic changes that occur during ID. Understanding the changes in metabolic substrate utilisation and their modification may provide potential for discovery of new biomarkers and therapeutic targets in cardiovascular diseases.

Keywords:  cardiomyocytes; iron deficiency; pluripotent stem cells

DOI:  https://doi.org/10.3390/metabo12010009
Biochim Biophys Acta Mol Cell Biol Lipids. 2022 Jan 17. pii: S1388-1981(21)00222-5. [Epub ahead of print] 159094

NAD supplementation improves mitochondrial performance of cardiolipin mutants.

Jiajia Ji, Deena Damschroder, Denise Bessert, Pablo Lazcano, Robert Wessells, Christian A Reynolds, Miriam L Greenberg.

  Cardiolipin (CL) deficiency causes mitochondrial dysfunction and aberrant metabolism that are associated in humans with the severe disease Barth syndrome (BTHS). Several metabolic abnormalities are observed in BTHS patients and model systems, including decreased oxidative phosphorylation, reduced tricarboxylic acid (TCA) cycle flux, and accumulated lactate and D-β-hydroxybutyrate, which strongly suggests that nicotinamide adenine dinucleotide (NAD) redox metabolism may be altered in CL-deficient cells. In this study, we identified abnormal NAD+ metabolism in multiple BTHS model systems and demonstrate that supplementation of NAD+ precursors such as nicotinamide mononucleotide (NMN) improves mitochondrial function. Improved mitochondrial function in the Drosophila model was associated with restored exercise endurance, which suggests a potential therapeutic benefit of NAD+ precursor supplementation in the management of BTHS patients.

Keywords:  Barth syndrome; Cardiolipin deficiency; Mitochondrial function; NAD(+) precursors; NAD(+) redox; Nicotinamide mononucleotide

DOI:  https://doi.org/10.1016/j.bbalip.2021.159094
Life Sci. 2022 Jan 17. pii: S0024-3205(22)00033-9. [Epub ahead of print] 120333

Effect of l-carnitine and mildronate on the mitochondrial metabolism of heart and bacterial composition of the gut microbiome in ageing mice.

Daria E Volodina, Artem P Gureev, Ekaterina A Shaforostova, Mariya V Gryaznova, Daria A Ignatyeva, Vasily N Popov.

  Ageing is the most significant risk factor for cardiovascular diseases. l-Carnitine has a potent cardioprotective effect and its synthesis decreases during ageing. At the same time, there are pharmaceuticals, such as mildronate which, on the contrary, are aimed at reducing the concentration of l-carnitine in the heart and lead to slows down the oxidation of fatty acids in mitochondria. Despite this, both l-carnitine and mildronate are positioned as cardio protectors. We showed that l-carnitine supplementation to the diet of 15-month-old mice increased expression of the PGC-1α gene, which is responsible for the regulation of fatty acid oxidation, and the Nrf2 gene, which is responsible for protecting mitochondria by regulating the expression of antioxidants and mitophagy, in the heart. Mildronate activated the expression of genes that regulate glucose metabolism. Probably, this metabolic shift may protect the mitochondria of the heart from the accumulation of acyl-carnitine, which occurs during the oxidation of fatty acids under oxygen deficiency. Both pharmaceuticals impacted the gut microbiome bacterial composition. l-Carnitine increased the level of Lachnoanaerobaculum and [Eubacterium] hallii group, mildronate increased the level of Bifidobacterium, Rikinella, Christensenellaceae. Considered, that these bacteria for protection the organism from various pathogens and chronic inflammation. Thus, we suggested that the positive effects of both drugs on the mitochondria metabolism and gut microbiome bacterial composition may contribute to the protection of the heart during ageing.

Keywords:  Ageing; Cardioprotectors; Fatty acid oxidation; Glucose oxidation; Gut microbiome; Metabolism; Mildronate; Mitochondria; l-Carnitine

DOI:  https://doi.org/10.1016/j.lfs.2022.120333
Oxid Med Cell Longev. 2022 ;2022 7105181

Melatonin Attenuates Ischemia/Reperfusion-Induced Oxidative Stress by Activating Mitochondrial Fusion in Cardiomyocytes.

Xiaoling Ma, Shengchi Wang, Hui Cheng, Haichun Ouyang, Xiaoning Ma.

Myocardial ischemia/reperfusion (I/R) injury can stimulate mitochondrial reactive oxygen species production. Optic atrophy 1- (OPA1-) induced mitochondrial fusion is an endogenous antioxidative mechanism that preserves the mitochondrial function. In our study, we investigated whether melatonin augments OPA1-dependent mitochondrial fusion and thus maintains redox balance during myocardial I/R injury. In hypoxia/reoxygenation- (H/R-) treated H9C2 cardiomyocytes, melatonin treatment upregulated OPA1 mRNA and protein expression, thereby enhancing mitochondrial fusion. Melatonin also suppressed apoptosis in H/R-treated cardiomyocytes, as evidenced by increased cell viability, diminished caspase-3 activity, and reduced Troponin T secretion; however, silencing OPA1 abolished these effects. H/R treatment augmented mitochondrial ROS production and repressed antioxidative molecule levels, while melatonin reversed these changes in an OPA1-dependent manner. Melatonin also inhibited mitochondrial permeability transition pore opening and maintained the mitochondrial membrane potential, but OPA1 silencing prevented these outcomes. These results illustrate that melatonin administration alleviates cardiomyocyte I/R injury by activating OPA1-induced mitochondrial fusion and inhibiting mitochondrial oxidative stress.

DOI: https://doi.org/10.1155/2022/7105181
Antioxid Redox Signal. 2022 Jan 19.

Inhibition of fatty acid translocase (FAT/CD36) palmitoylation enhances hepatic fatty acid β-oxidation by increasing its localization to mitochondria and interaction with long-chain acyl-CoA synthetase 1.

Shu Zeng, Fan Wu, Mengyue Chen, Yun Li, Mengyue You, Yang Zhang, Ping Yang, Li Wei, Xiong Z Ruan, Lei Zhao, Yaxi Chen.

AIMS: Impaired fatty acid oxidation (FAO) in mitochondria of hepatocytes causes lipid accumulation and excessive production of ROS and oxidative damage, as a result leads to nonalcoholic fatty liver disease (NAFLD). Fatty acid translocase (FAT/CD36), a transmembrane protein that facilitates the uptake of long-chain fatty acids (LCFAs), is recently found to be involved in FAO. The function of FAT/CD36 is associated with its subcellular localization. Palmitoylation, one of the most common lipid modifications, is generally thought to regulate FAT/CD36 subcellular localization. Here, we aimed to investigate the role of palmitoylation in FAT/CD36 localization to mitochondria and its influence on FAO in hepatocytes.
RESULTS: We demonstrated that FAT/CD36 exists on the mitochondria of hepatocytes. Palmitoylation of FAT/CD36 was significantly up-regulated in NAFLD. Inhibition of FAT/CD36 palmitoylation resulted in an obvious increase in the distribution of FAT/CD36 to mitochondria of hepatocytes. Depalmitoylated FAT/CD36 on the mitochondrial membrane continues functioning by facilitating fatty acid trafficking to mitochondria. Abundant mitochondrial FAT/CD36 interacted with long-chain acyl-CoA synthetase 1 (ACSL1), and thus, more LCFAs were transported to ACSL1. This led to an increase in the generation of long-chain acyl-CoA, contributing to the enhancement of FAO and alleviating NAFLD. Innovation and Conclusion: This work revealed that inhibiting FAT/CD36 palmitoylation alleviates NAFLD by promoting FAT/CD36 localization to the mitochondria of hepatocytes. Mitochondrial FAT/CD36 functions as a molecular bridge between LCFAs and ACSL1 to increase the production of long-chain acyl-CoA thus promoting FAO, thereby avoiding lipid accumulation and over-production of ROS in hepatocytes.

DOI: https://doi.org/10.1089/ars.2021.0157
Plants (Basel). 2022 Jan 13. pii: 199. [Epub ahead of print]11(2):

Metabolic and Physiological Regulation of Aspartic Acid-Mediated Enhancement of Heat Stress Tolerance in Perennial Ryegrass.

Shuhan Lei, Stephanie Rossi, Bingru Huang.

  Aspartate is the most critical amino acid in the aspartate metabolic pathway, which is associated with multiple metabolic pathways, such as protein synthesis, nucleotide metabolism, TCA cycle, glycolysis, and hormone biosynthesis. Aspartate also plays an important role in plant resistance to abiotic stress, such as cold stress, drought stress, salt stress or heavy metal stress. This study found that the chlorophyll content and antioxidant active enzyme content (SOD, CAT, POD and APX) of perennial ryegrass treated with 2 mM aspartate were significantly higher than those treated with water under heat stress. The electrolyte leakage rate, MDA content and peroxide levels (O2- and H2O2) of perennial ryegrass treated with aspartate were significantly lower than those of perennial ryegrass treated with water, indicating that exogenous aspartate increases the content of chlorophyll, maintain the integrity of cell membrane system, and enhances SOD-CAT antioxidant pathway to eliminate the oxidative damage caused by ROS in perennial ryegrass under heat stress. Furthermore, exogenous aspartate could enhance the TCA cycle, the metabolism of the amino acids related to the TCA cycle, and pyrimidine metabolism to enhance the heat tolerance of perennial ryegrass.

Keywords:  aspartate; heat stress; metabolites; perennial ryegrass

DOI:  https://doi.org/10.3390/plants11020199
Biochim Biophys Acta Bioenerg. 2022 Jan 18. pii: S0005-2728(22)00001-9. [Epub ahead of print] 148532

MDH2 produced OAA is a metabolic switch rewiring the fuelling of respiratory chain and TCA cycle.

Thibaut Molinié, Elodie Cougouilles, Claudine David, Edern Cahoreau, Jean-Charles Portais, Arnaud Mourier.

  The mitochondrial respiratory chain (RC) enables many metabolic processes by regenerating both mitochondrial and cytosolic NAD+ and ATP. The oxidation by the RC of the NADH metabolically produced in the cytosol involves redox shuttles as the malate-aspartate shuttle (MAS) and is of paramount importance for cell fate. However, the specific metabolic regulations allowing mitochondrial respiration to prioritize NADH oxidation in response to high NADH/NAD+ redox stress have not been elucidated. The recent discovery that complex I (NADH dehydrogenase), and not complex II (Succinate dehydrogenase), can assemble with other respiratory chain (RC) complexes to form functional entities called respirasomes, led to the assumption that this supramolecular organization would favour NADH oxidation. Unexpectedly, characterization of heart and liver mitochondria demonstrates that the RC systematically favours electrons provided by the 'respirasome free' complex II. Our results demonstrate that the preferential succinate driven respiration is tightly controlled by OAA levels, and that OAA feedback inhibition of complex II rewires RC fuelling increasing NADH oxidation capacity. This new regulatory mechanism synergistically increases RC's NADH oxidative capacity and rewires MDH2 driven anaplerosis of the TCA, preventing malate production from succinate to favour oxidation of cytosolic malate. This regulatory mechanism synergistically adjusts RC and TCA fuelling in response to extramitochondrial malate produced by the MAS.

Keywords:  Bioenergetics; MDH2; Malate aspartate shuttle; Mitochondria; NADH redox homeostasis; Oxaloacetate; Respirasomes; Respiratory chain supercomplexes

DOI:  https://doi.org/10.1016/j.bbabio.2022.148532
Int J Mol Sci. 2022 Jan 16. pii: 952. [Epub ahead of print]23(2):

The Role of Mitochondrial DNA Mutations in Cardiovascular Diseases.

Siarhei A Dabravolski, Victoria A Khotina, Vasily N Sukhorukov, Vladislav A Kalmykov, Liudmila M Mikhaleva, Alexander N Orekhov.

  Cardiovascular diseases (CVD) are one of the leading causes of morbidity and mortality worldwide. mtDNA (mitochondrial DNA) mutations are known to participate in the development and progression of some CVD. Moreover, specific types of mitochondria-mediated CVD have been discovered, such as MIEH (maternally inherited essential hypertension) and maternally inherited CHD (coronary heart disease). Maternally inherited mitochondrial CVD is caused by certain mutations in the mtDNA, which encode structural mitochondrial proteins and mitochondrial tRNA. In this review, we focus on recently identified mtDNA mutations associated with CVD (coronary artery disease and hypertension). Additionally, new data suggest the role of mtDNA mutations in Brugada syndrome and ischemic stroke, which before were considered only as a result of mutations in nuclear genes. Moreover, we discuss the molecular mechanisms of mtDNA involvement in the development of the disease.

Keywords:  Brugada syndrome; atherosclerosis; cardiovascular diseases; coronary artery disease; hypertension; ischemic stroke; mitochondria

DOI:  https://doi.org/10.3390/ijms23020952
Oxid Med Cell Longev. 2022 ;2022 7714542

The Oxidative Balance Orchestrates the Main Keystones of the Functional Activity of Cardiomyocytes.

Michele Bevere, Caterina Morabito, Maria A Mariggiò, Simone Guarnieri.

This review is aimed at providing an overview of the key hallmarks of cardiomyocytes in physiological and pathological conditions. The main feature of cardiac tissue is the force generation through contraction. This process requires a conspicuous energy demand and therefore an active metabolism. The cardiac tissue is rich of mitochondria, the powerhouses in cells. These organelles, producing ATP, are also the main sources of ROS whose altered handling can cause their accumulation and therefore triggers detrimental effects on mitochondria themselves and other cell components thus leading to apoptosis and cardiac diseases. This review highlights the metabolic aspects of cardiomyocytes and wanders through the main systems of these cells: (a) the unique structural organization (such as different protein complexes represented by contractile, regulatory, and structural proteins); (b) the homeostasis of intracellular Ca2+ that represents a crucial ion for cardiac functions and E-C coupling; and (c) the balance of Zn2+, an ion with a crucial impact on the cardiovascular system. Although each system seems to be independent and finely controlled, the contractile proteins, intracellular Ca2+ homeostasis, and intracellular Zn2+ signals are strongly linked to each other by the intracellular ROS management in a fascinating way to form a "functional tetrad" which ensures the proper functioning of the myocardium. Nevertheless, if ROS balance is not properly handled, one or more of these components could be altered resulting in deleterious effects leading to an unbalance of this "tetrad" and promoting cardiovascular diseases. In conclusion, this "functional tetrad" is proposed as a complex network that communicates continuously in the cardiomyocytes and can drive the switch from physiological to pathological conditions in the heart.

DOI: https://doi.org/10.1155/2022/7714542