bims-mimcad Biomed News
on Mitochondrial metabolism and cardiometabolic diseases
Issue of 2024–09–15
nine papers selected by
Henver Brunetta, Karolinska Institutet
  1. Effect of Weight Loss on Skeletal Muscle Bioactive Lipids in People with Obesity and Type 2 Diabetes.
  2. An intrinsic mechanism of metabolic tuning promotes cardiac resilience to stress.
  3. KLF3 impacts insulin sensitivity and glucose uptake in skeletal muscle.
  4. Endothelial metabolic control of insulin sensitivity through resident macrophages.
  5. Years of endurance exercise training remodel abdominal subcutaneous adipose tissue in adults with overweight or obesity.
  6. Organization of a functional glycolytic metabolon on mitochondria for metabolic efficiency.
  7. IRS2 Signaling Protects Against Stress-Induced Arrhythmia by Maintaining Ca2+ Homeostasis.
  8. Haplotype variability in mitochondrial rRNA predisposes to metabolic syndrome.
  9. Murine Nuclear Tyrosyl-tRNA Synthetase Deficiency Leads to Fat Storage Deficiency and Hearing Loss.
  1. Diabetes. 2024 Sep 12. pii: db240083. [Epub ahead of print]
    Effect of Weight Loss on Skeletal Muscle Bioactive Lipids in People with Obesity and Type 2 Diabetes.
    Max C Petersen, Mihoko Yoshino, Gordon I Smith, Rafael C Gaspar, Mario Kahn, Dmitri Samovski, Gerald I Shulman, Samuel Klein.
      Muscle sn-1,2-diacylglycerol (DAG) and C18:0 ceramide accumulation in sarcolemmal and mitochondrial compartments have been proposed to regulate muscle insulin sensitivity. Here, we evaluated whether weight loss-induced improvements in insulin sensitivity were associated with changes in muscle sn-1,2-DAG and ceramide content in people with obesity and type 2 diabetes. We measured skeletal muscle insulin sensitivity, assessed by using the hyperinsulinemic-euglycemic clamp procedure in conjunction with stable isotopically labeled glucose tracer infusion, and skeletal muscle sn-1,2-DAG and ceramide contents by using liquid chromatography-tandem mass spectrometry after subcellular fractionation and DAG isomer separation in 14 adults with obesity and type 2 diabetes before and after marked (18.6 ± 2.1%) weight loss. Whole-body insulin sensitivity doubled after weight loss. Sarcolemmal sn-1,2-DAG and C18:0 ceramide contents after weight loss were not different than values before weight loss. In contrast, mitochondrial/ER C18:0 ceramide content decreased by ∼20% after weight loss (from 2.16 ± 0.08 to 1.71 ± 0.13 nmol/g, P<0.005). These results suggest a decrease in muscle mitochondrial/ER C18:0 ceramide content could contribute to the beneficial effect of weight loss on skeletal muscle insulin sensitivity.
    DOI:  https://doi.org/10.2337/db24-0083
  2. EMBO Mol Med. 2024 Sep 13.
    An intrinsic mechanism of metabolic tuning promotes cardiac resilience to stress.
    Matteo Sorge, Giulia Savoré, Andrea Gallo, Davide Acquarone, Mauro Sbroggiò, Silvia Velasco, Federica Zamporlini, Saveria Femminò, Enrico Moiso, Giampaolo Morciano, Elisa Balmas, Andrea Raimondi, Gabrielle Nattenberg, Rachele Stefania, Carlo Tacchetti, Angela Maria Rizzo, Paola Corsetto, Alessandra Ghigo, Emilia Turco, Fiorella Altruda, Lorenzo Silengo, Paolo Pinton, Nadia Raffaelli, Nathan J Sniadecki, Claudia Penna, Pasquale Pagliaro, Emilio Hirsch, Chiara Riganti, Guido Tarone, Alessandro Bertero, Mara Brancaccio.
      Defining the molecular mechanisms underlying cardiac resilience is crucial to find effective approaches to protect the heart. A physiologic level of ROS is produced in the heart by fatty acid oxidation, but stressful events can boost ROS and cause mitochondrial dysfunction and cardiac functional impairment. Melusin is a muscle specific chaperone required for myocardial compensatory remodeling during stress. Here we report that Melusin localizes in mitochondria where it binds the mitochondrial trifunctional protein, a key enzyme in fatty acid oxidation, and decreases it activity. Studying both mice and human induced pluripotent stem cell-derived cardiomyocytes, we found that Melusin reduces lipid oxidation in the myocardium and limits ROS generation in steady state and during pressure overload and doxorubicin treatment, preventing mitochondrial dysfunction. Accordingly, the treatment with the lipid oxidation inhibitor Trimetazidine concomitantly with stressful stimuli limits ROS accumulation and prevents long-term heart dysfunction. These findings disclose a physiologic mechanism of metabolic regulation in the heart and demonstrate that a timely restriction of lipid metabolism represents a potential therapeutic strategy to improve cardiac resilience to stress.
    Keywords:  Cardiac Metabolism; Chaperone Proteins; Doxorubicin; Pressure Overload; ROS
    DOI:  https://doi.org/10.1038/s44321-024-00132-z
  3. Am J Physiol Cell Physiol. 2024 Sep 09.
    KLF3 impacts insulin sensitivity and glucose uptake in skeletal muscle.
    Shuying Fu, Xiaocheng Gong, Keying Liang, Ke Ding, Li Qiu, Huice Cen, Hongli Du.
      Skeletal muscle is one of the predominant sites involved in glucose disposal, accounting for approximately 80% of postprandial glucose uptake, and plays a critical role in maintaining glycemic homeostasis. Dysregulation of energy metabolism in skeletal muscle is involved in developing insulin resistance and type 2 diabetes (T2D). Transcriptomic responses of skeletal muscle to exercise found that the expression of Klf3 was increased in T2D Goto-Kakizaki (GK) rats and decreased after exercise with improved hyperglycemia and insulin resistance, implying that Klf3 might be associated with insulin sensitivity and glucose metabolism. We also found that knockdown of Klf3 promoted basal and insulin-stimulated glucose uptake in L6 myotubes, while overexpression of Klf3 resulted in the opposite. Through pairwise comparisons of L6 myotubes transcriptome, we identified 2256 and 1988 differentially expressed genes in Klf3 knockdown and overexpression groups, respectively. In insulin signaling, the expression of Slc2a4, Akt2, Insr and Sorbs1 was significantly increased by Klf3 knockdown and decreased with klf3 overexpression; Ptprf and Fasn were markedly downregulated in klf3 reduced group and upregulated in klf3 overexpressed group. Moreover, downregulation of Klf3 promoted the expression of GLUT4 and AKT proteins, as well as the translocation of GLUT4 to the cell membrane in the basal situation, and enhanced insulin sensitivity, characterized by increased insulin-stimulated GLUT4 translocation and AKT, TBC1D1 and TBC1D4 phosphorylation, while overexpression of Klf3 showed contrary results. These results suggest that Klf3 affects glucose uptake and insulin sensitivity via insulin signal transduction and intracellular metabolism, offering a novel potential treatment strategy for T2D.
    Keywords:  Krüppel-Like Factor 3 (KLF3); L6 myotube; glucose uptake; insulin resistance; skeletal muscle
    DOI:  https://doi.org/10.1152/ajpcell.00085.2024
  4. Cell Metab. 2024 Sep 08. pii: S1550-4131(24)00335-8. [Epub ahead of print]
    Endothelial metabolic control of insulin sensitivity through resident macrophages.
    Jing Zhang, Kim Anker Sjøberg, Songlin Gong, Tongtong Wang, Fengqi Li, Andrew Kuo, Stephan Durot, Adam Majcher, Raphaela Ardicoglu, Thibaut Desgeorges, Charlotte Greta Mann, Ines Soro Arnáiz, Gillian Fitzgerald, Paola Gilardoni, E Dale Abel, Shigeyuki Kon, Danyvid Olivares-Villagómez, Nicola Zamboni, Christian Wolfrum, Thorsten Hornemann, Raphael Morscher, Nathalie Tisch, Bart Ghesquière, Manfred Kopf, Erik A Richter, Katrien De Bock.
      Endothelial cells (ECs) not only form passive blood conduits but actively contribute to nutrient transport and organ homeostasis. The role of ECs in glucose homeostasis is, however, poorly understood. Here, we show that, in skeletal muscle, endothelial glucose transporter 1 (Glut1/Slc2a1) controls glucose uptake via vascular metabolic control of muscle-resident macrophages without affecting transendothelial glucose transport. Lowering endothelial Glut1 via genetic depletion (Glut1ΔEC) or upon a short-term high-fat diet increased angiocrine osteopontin (OPN/Spp1) secretion. This promoted resident muscle macrophage activation and proliferation, which impaired muscle insulin sensitivity. Consequently, co-deleting Spp1 from ECs prevented macrophage accumulation and improved insulin sensitivity in Glut1ΔEC mice. Mechanistically, Glut1-dependent endothelial glucose metabolic rewiring increased OPN in a serine metabolism-dependent fashion. Our data illustrate how the glycolytic endothelium creates a microenvironment that controls resident muscle macrophage phenotype and function and directly links resident muscle macrophages to the maintenance of muscle glucose homeostasis.
    Keywords:  GLUT1; endothelial cells; endothelial metabolism; inflammation; insulin sensitivity; osteopontin; resident macrophages; serine; skeletal muscle; vasculature
    DOI:  https://doi.org/10.1016/j.cmet.2024.08.008
  5. Nat Metab. 2024 Sep 10.
    Years of endurance exercise training remodel abdominal subcutaneous adipose tissue in adults with overweight or obesity.
    Cheehoon Ahn, Tao Zhang, Gayoung Yang, Thomas Rode, Pallavi Varshney, Sophia J Ghayur, Olivia K Chugh, Hui Jiang, Jeffrey F Horowitz.
      Abnormalities in the structure and metabolic function of abdominal subcutaneous adipose tissue (aSAT) underlie many obesity-related health complications. Endurance exercise improves cardiometabolic health in adults with overweight or obesity, but the effects of endurance training on aSAT are unclear. We included male and female participants who were regular exercisers with overweight or obesity who exercised for >2 years, and cross-sectionally compared them with well-matched non-exercisers with overweight or obesity. Here we show aSAT from exercisers has a higher capillary density, lower Col6a abundance and fewer macrophages compared with non-exercisers. This is accompanied by a greater abundance of angiogenic, ribosomal, mitochondrial and lipogenic proteins. The abundance of phosphoproteins involved in protein translation, lipogenesis and direct regulation of transcripts is also greater in aSAT collected from exercisers. Exploratory ex vivo experiments demonstrate greater angiogenic capacity and higher lipid-storage capacity in samples cultured from aSAT collected from exercisers versus non-exercisers. Regular exercise may play a role in remodelling aSAT structure and proteomic profile in ways that may contribute to preserved cardiometabolic health.
    DOI:  https://doi.org/10.1038/s42255-024-01103-x
  6. Nat Metab. 2024 Sep 11.
    Organization of a functional glycolytic metabolon on mitochondria for metabolic efficiency.
    Haoming Wang, John W Vant, Andrew Zhang, Richard G Sanchez, Youjun Wu, Mary L Micou, Vincent Luczak, Zachary Whiddon, Natasha M Carlson, Seungyoon B Yu, Mirna Jabbo, Seokjun Yoon, Ahmed A Abushawish, Majid Ghassemian, Takeya Masubuchi, Quan Gan, Shigeki Watanabe, Eric R Griffis, Marc Hammarlund, Abhishek Singharoy, Gulcin Pekkurnaz.
      Glucose, the primary cellular energy source, is metabolized through glycolysis initiated by the rate-limiting enzyme hexokinase (HK). In energy-demanding tissues like the brain, HK1 is the dominant isoform, primarily localized on mitochondria, and is crucial for efficient glycolysis-oxidative phosphorylation coupling and optimal energy generation. This study unveils a unique mechanism regulating HK1 activity, glycolysis and the dynamics of mitochondrial coupling, mediated by the metabolic sensor enzyme O-GlcNAc transferase (OGT). OGT catalyses reversible O-GlcNAcylation, a post-translational modification influenced by glucose flux. Elevated OGT activity induces dynamic O-GlcNAcylation of the regulatory domain of HK1, subsequently promoting the assembly of the glycolytic metabolon on the outer mitochondrial membrane. This modification enhances the mitochondrial association with HK1, orchestrating glycolytic and mitochondrial ATP production. Mutation in HK1's O-GlcNAcylation site reduces ATP generation in multiple cell types, specifically affecting metabolic efficiency in neurons. This study reveals a previously unappreciated pathway that links neuronal metabolism and mitochondrial function through OGT and the formation of the glycolytic metabolon, providing potential strategies for tackling metabolic and neurological disorders.
    DOI:  https://doi.org/10.1038/s42255-024-01121-9
  7. Circulation. 2024 Sep 10.
    IRS2 Signaling Protects Against Stress-Induced Arrhythmia by Maintaining Ca2+ Homeostasis.
    Qian Shi, Jinxi Wang, Hamza Malik, Xuguang Li, Jennifer Streeter, Jacob Sharafuddin, Eric Weatherford, David Stein, Yuval Itan, Biyi Chen, Duane Hall, Long-Sheng Song, E Dale Abel.
       BACKGROUND: The docking protein IRS2 (insulin receptor substrate protein-2) is an important mediator of insulin signaling and may also regulate other signaling pathways. Murine hearts with cardiomyocyte-restricted deletion of IRS2 (cIRS2-KO) are more susceptible to pressure overload-induced cardiac dysfunction, implying a critical protective role of IRS2 in cardiac adaptation to stress through mechanisms that are not fully understood. There is limited evidence regarding the function of IRS2 beyond metabolic homeostasis regulation, particularly in the context of cardiac disease.
    METHODS: A retrospective analysis of an electronic medical record database was conducted to identify patients with IRS2 variants and assess their risk of cardiac arrhythmias. Arrhythmia susceptibility was examined in cIRS2-KO mice. The underlying mechanisms were investigated using confocal calcium imaging of ex vivo whole hearts and isolated cardiomyocytes to assess calcium handling, Western blotting to analyze the involved signaling pathways, and pharmacological and genetic interventions to rescue arrhythmias in cIRS2-KO mice.
    RESULTS: The retrospective analysis identified patients with IRS2 variants of uncertain significance with a potential association to an increased risk of cardiac arrhythmias compared with matched controls. cIRS2-KO hearts were found to be prone to catecholamine-sensitive ventricular tachycardia and reperfusion ventricular tachycardia. Confocal calcium imaging of ex vivo whole hearts and single isolated cardiomyocytes from cIRS2-KO hearts revealed decreased Ca²+ transient amplitudes, increased spontaneous Ca²+ sparks, and reduced sarcoplasmic reticulum Ca²+ content during sympathetic stress, indicating sarcoplasmic reticulum dysfunction. We identified that overactivation of the AKT1/NOS3 (nitric oxide synthase 3)/CaMKII (Ca2+/calmodulin-dependent protein kinase II)/RyR2 (type 2 ryanodine receptor) signaling pathway led to calcium mishandling and catecholamine-sensitive ventricular tachycardia in cIRS2-KO hearts. Pharmacological AKT inhibition or genetic stabilization of RyR2 rescued catecholamine-sensitive ventricular tachycardia in cIRS2-KO mice.
    CONCLUSIONS: Cardiac IRS2 inhibits sympathetic stress-induced AKT/NOS3/CaMKII/RyR2 overactivation and calcium-dependent arrhythmogenesis. This novel IRS2 signaling axis, essential for maintaining cardiac calcium homeostasis under stress, presents a promising target for developing new antiarrhythmic therapies.
    Keywords:  arrhythmias, cardiac; calcium; calcium-calmodulin-dependent protein kinase type 2; insulin receptor substrate proteins; ryanodine receptor calcium release channel
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.123.065048
  8. Commun Biol. 2024 Sep 11. 7(1): 1116
    Haplotype variability in mitochondrial rRNA predisposes to metabolic syndrome.
    Petr Pecina, Kristýna Čunátová, Vilma Kaplanová, Guillermo Puertas-Frias, Jan Šilhavý, Kateřina Tauchmannová, Marek Vrbacký, Tomáš Čajka, Ondřej Gahura, Markéta Hlaváčková, Viktor Stránecký, Stanislav Kmoch, Michal Pravenec, Josef Houštěk, Tomáš Mráček, Alena Pecinová.
      Metabolic syndrome is a growing concern in developed societies and due to its polygenic nature, the genetic component is only slowly being elucidated. Common mitochondrial DNA sequence variants have been associated with symptoms of metabolic syndrome and may, therefore, be relevant players in the genetics of metabolic syndrome. We investigate the effect of mitochondrial sequence variation on the metabolic phenotype in conplastic rat strains with identical nuclear but unique mitochondrial genomes, challenged by high-fat diet. We find that the variation in mitochondrial rRNA sequence represents risk factor in the insulin resistance development, which is associated with diacylglycerols accumulation, induced by tissue-specific reduction of the oxidative capacity. These metabolic perturbations stem from the 12S rRNA sequence variation affecting mitochondrial ribosome assembly and translation. Our work demonstrates that physiological variation in mitochondrial rRNA might represent a relevant underlying factor in the progression of metabolic syndrome.
    DOI:  https://doi.org/10.1038/s42003-024-06819-w
  9. J Biol Chem. 2024 Sep 09. pii: S0021-9258(24)02257-9. [Epub ahead of print] 107756
    Murine Nuclear Tyrosyl-tRNA Synthetase Deficiency Leads to Fat Storage Deficiency and Hearing Loss.
    Julia A Jones, Jiadong Zhou, Jianjie Dong, Salvador Huitron-Resendiz, Ely Boussaty, Eduardo Chavez, Na Wei, Calin Dan Dumitru, Yosuke Morodomi, Taisuke Kanaji, Allen F Ryan, Rick Friedman, Tong Zhou, Sachiko Kanaji, Matthew Wortham, Simon Schenk, Amanda J Roberts, Xiang-Lei Yang.
      Aminoacyl-tRNA synthetases (aaRS) are fundamental to the translation machinery with emerging roles in transcriptional regulation. Previous cellular studies have demonstrated tyrosyl-tRNA synthetase (YARS1 or TyrRS) as a stress response protein through its cytosol-nucleus translocation to maintain cellular homeostasis. Here, we established a mouse model with a disrupted TyrRS nuclear localization signal, revealing its systemic impact on metabolism. Nuclear TyrRS deficiency (YarsΔNLS) led to reduced lean mass, reflecting a mild developmental defect, and reduced fat mass, possibly due to increased energy expenditure. Consistently, YarsΔNLS mice exhibit improved insulin sensitivity and reduced insulin levels, yet maintain normoglycemia, indicative of enhanced insulin action. Notably, YarsΔNLS mice also develop progressive hearing loss. These findings underscore the crucial function of nuclear TyrRS in the maintenance of fat storage and hearing and suggest that aaRSs' regulatory roles can affect metabolic pathways and tissue-specific health. This work broadens our understanding of how protein synthesis interconnects metabolic regulation to ensure energy efficiency.
    Keywords:  adipose tissue; aminoacyl tRNA synthetase; hearing; insulin; metabolism
    DOI:  https://doi.org/10.1016/j.jbc.2024.107756
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