bims-mimcad Biomed News
on Mitochondrial metabolism and cardiometabolic diseases
Issue of 2024‒06‒09
six papers selected by
Henver Brunetta, University of Guelph
  1. Semaglutide ameliorates cardiac remodeling in male mice by optimizing energy substrate utilization through the Creb5/NR4a1 axis.
  2. Empagliflozin Improves Diastolic Function in HFpEF by Restabilizing the Mitochondrial Respiratory Chain.
  3. Skeletal muscle PGC-1α remodels mitochondrial phospholipidome but does not alter energy efficiency for ATP synthesis.
  4. Mitochondrial glycerol 3-phosphate dehydrogenase deficiency exacerbates lipotoxic cardiomyopathy.
  5. Pyroptosis and mitochondrial function participated in miR-654-3p-protected against myocardial infarction.
  6. LncRNA DCRT Protects Against Dilated Cardiomyopathy by Preventing NDUFS2 Alternative Splicing by Binding to PTBP1.
  1. Nat Commun. 2024 Jun 04. 15(1): 4757
    Semaglutide ameliorates cardiac remodeling in male mice by optimizing energy substrate utilization through the Creb5/NR4a1 axis.
    Yu-Lan Ma, Chun-Yan Kong, Zhen Guo, Ming-Yu Wang, Pan Wang, Fang-Yuan Liu, Dan Yang, Zheng Yang, Qi-Zhu Tang.
      Semaglutide, a glucagon-like peptide-1 receptor agonist, is clinically used as a glucose-lowering and weight loss medication due to its effects on energy metabolism. In heart failure, energy production is impaired due to altered mitochondrial function and increased glycolysis. However, the impact of semaglutide on cardiomyocyte metabolism under pressure overload remains unclear. Here we demonstrate that semaglutide improves cardiac function and reduces hypertrophy and fibrosis in a mouse model of pressure overload-induced heart failure. Semaglutide preserves mitochondrial structure and function under chronic stress. Metabolomics reveals that semaglutide reduces mitochondrial damage, lipid accumulation, and ATP deficiency by promoting pyruvate entry into the tricarboxylic acid cycle and increasing fatty acid oxidation. Transcriptional analysis shows that semaglutide regulates myocardial energy metabolism through the Creb5/NR4a1 axis in the PI3K/AKT pathway, reducing NR4a1 expression and its translocation to mitochondria. NR4a1 knockdown ameliorates mitochondrial dysfunction and abnormal glucose and lipid metabolism in the heart. These findings suggest that semaglutide may be a therapeutic agent for improving cardiac remodeling by modulating energy metabolism.
    DOI:  https://doi.org/10.1038/s41467-024-48970-2
  2. Circ Heart Fail. 2024 Jun 07. e011107
    Empagliflozin Improves Diastolic Function in HFpEF by Restabilizing the Mitochondrial Respiratory Chain.
    Antje Schauer, Volker Adams, Susanne Kämmerer, Erik Langner, Antje Augstein, Peggy Barthel, Anita Männel, Gunar Fabig, Paula Ketilly Nascimento Alves, Mario Günscht, Ali El-Armouche, Thomas Müller-Reichert, Axel Linke, Ephraim B Winzer.
      BACKGROUND: Clinical studies demonstrated beneficial effects of sodium-glucose-transporter 2 inhibitors on the risk of cardiovascular death in patients with heart failure with preserved ejection fraction (HFpEF). However, underlying processes for cardioprotection remain unclear. The present study focused on the impact of empagliflozin (Empa) on myocardial function in a rat model with established HFpEF and analyzed underlying molecular mechanisms.METHODS: Obese ZSF1 (Zucker fatty and spontaneously hypertensive) rats were randomized to standard care (HFpEF, n=18) or Empa (HFpEF/Empa, n=18). ZSF1 lean rats (con, n=18) served as healthy controls. Echocardiography was performed at baseline and after 4 and 8 weeks, respectively. After 8 weeks of treatment, hemodynamics were measured invasively, mitochondrial function was assessed and myocardial tissue was collected for either molecular and histological analyses or transmission electron microscopy.
    RESULTS: In HFpEF Empa significantly improved diastolic function (E/é: con: 17.5±2.8; HFpEF: 24.4±4.6; P<0.001 versus con; HFpEF/Empa: 19.4±3.2; P<0.001 versus HFpEF). This was accompanied by improved hemodynamics and calcium handling and by reduced inflammation, hypertrophy, and fibrosis. Proteomic analysis demonstrated major changes in proteins involved in mitochondrial oxidative phosphorylation. Cardiac mitochondrial respiration was significantly impaired in HFpEF but restored by Empa (Vmax complex IV: con: 0.18±0.07 mmol O2/s/mg; HFpEF: 0.13±0.05 mmol O2/s/mg; P<0.041 versus con; HFpEF/Empa: 0.21±0.05 mmol O2/s/mg; P=0.012 versus HFpEF) without alterations of mitochondrial content. The expression of cardiolipin, an essential stability/functionality-mediating phospholipid of the respiratory chain, was significantly decreased in HFpEF but reverted by Empa (con: 15.9±1.7 nmol/mg protein; HFpEF: 12.5±1.8 nmol/mg protein; P=0.002 versus con; HFpEF/Empa: 14.5±1.8 nmol/mg protein; P=0.03 versus HFpEF). Transmission electron microscopy revealed a reduced size of mitochondria in HFpEF, which was restored by Empa.
    CONCLUSIONS: The study demonstrates beneficial effects of Empa on diastolic function, hemodynamics, inflammation, and cardiac remodeling in a rat model of HFpEF. These effects were mediated by improved mitochondrial respiratory capacity due to modulated cardiolipin and improved calcium handling.
    Keywords:  cardiolipins; empagliflozin; heart failure; hypertension; inflammation
    DOI:  https://doi.org/10.1161/CIRCHEARTFAILURE.123.011107
  3. bioRxiv. 2024 May 26. pii: 2024.05.22.595374. [Epub ahead of print]
    Skeletal muscle PGC-1α remodels mitochondrial phospholipidome but does not alter energy efficiency for ATP synthesis.
    Takuya Karasawa, Ran Hee Choi, Cesar A Meza, J Alan Maschek, James E Cox, Katsuhiko Funai.
      Background: Exercise training is thought to improve the mitochondrial energy efficiency of skeletal muscle. Some studies suggest exercise training increases the efficiency for ATP synthesis by oxidative phosphorylation (OXPHOS), but the molecular mechanisms are unclear. We have previously shown that exercise remodels the lipid composition of mitochondrial membranes, and some of these changes could contribute to improved OXPHOS efficiency (ATP produced by O2 consumed or P/O). Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) is a transcriptional co-activator that coordinately regulates exercise-induced adaptations including mitochondria. We hypothesized that increased PGC-1α activity is sufficient to remodel mitochondrial membrane lipids and promote energy efficiency.Methods: Mice with skeletal muscle-specific overexpression of PGC-1α (MCK-PGC-1α) and their wildtype littermates were used for this study. Lipid mass spectrometry and quantitative PCR were used to assess muscle mitochondrial lipid composition and their biosynthesis pathway. The abundance of OXPHOS enzymes was determined by western blot assay. High-resolution respirometry and fluorometry analysis were used to characterize mitochondrial bioenergetics (ATP production, O2 consumption, and P/O) for permeabilized fibers and isolated mitochondria.
    Results: Lipidomic analyses of skeletal muscle mitochondria from wildtype and MCK-PGC-1α mice revealed that PGC-1α increases the concentrations of cone-shaped lipids such as phosphatidylethanolamine (PE), cardiolipin (CL), and lysophospholipids, while decreases the concentrations of phosphatidylcholine (PC), phosphatidylinositol (PI) and phosphatidic acid (PA). However, while PGC-1α overexpression increased the abundance of OXPHOS enzymes in skeletal muscle and the rate of O2 consumption (JO2), P/O values were unaffected with PGC-1α in permeabilized fibers or isolated mitochondria.
    Conclusions: Collectively, overexpression of PGC-1α promotes the biosynthesis of mitochondrial PE and CL but neither PGC-1α nor the mitochondrial membrane lipid remodeling induced in MCK-PGC-1α mice is sufficient to increase the efficiency for mitochondrial ATP synthesis. These findings suggest that exercise training may increase OXPHOS efficiency by a PGC-1α-independent mechanism, and question the hypothesis that mitochondrial lipids directly affect OXPHOS enzymes to improve efficiency for ATP synthesis.
    Keywords:  exercise; mitochondria; phospholipids; skeletal muscle
    DOI:  https://doi.org/10.1101/2024.05.22.595374
  4. iScience. 2024 Jun 21. 27(6): 109796
    Mitochondrial glycerol 3-phosphate dehydrogenase deficiency exacerbates lipotoxic cardiomyopathy.
    Hua Qu, Xiufei Liu, Jiaran Zhu, Niexia He, Qingshan He, Linlin Zhang, Yuren Wang, Xiaoli Gong, Xin Xiong, Jinbo Liu, Chuan Wang, Gangyi Yang, Qingwu Yang, Gang Luo, Zhiming Zhu, Yi Zheng, Hongting Zheng.
      Metabolic diseases such as obesity and diabetes induce lipotoxic cardiomyopathy, which is characterized by myocardial lipid accumulation, dysfunction, hypertrophy, fibrosis and mitochondrial dysfunction. Here, we identify that mitochondrial glycerol 3-phosphate dehydrogenase (mGPDH) is a pivotal regulator of cardiac fatty acid metabolism and function in the setting of lipotoxic cardiomyopathy. Cardiomyocyte-specific deletion of mGPDH promotes high-fat diet induced cardiac dysfunction, pathological hypertrophy, myocardial fibrosis, and lipid accumulation. Mechanically, mGPDH deficiency inhibits the expression of desuccinylase SIRT5, and in turn, the hypersuccinylates majority of enzymes in the fatty acid oxidation (FAO) cycle and promotes the degradation of these enzymes. Moreover, manipulating SIRT5 abolishes the effects of mGPDH ablation or overexpression on cardiac function. Finally, restoration of mGPDH improves lipid accumulation and cardiomyopathy in both diet-induced and genetic obese mouse models. Thus, our study indicates that targeting mGPDH could be a promising strategy for lipotoxic cardiomyopathy in the context of obesity and diabetes.
    Keywords:  biological sciences; cell biology; cellular physiology; diabetology; endocrinology; natural sciences; pathophysiology; physiology
    DOI:  https://doi.org/10.1016/j.isci.2024.109796
  5. Cell Death Dis. 2024 Jun 04. 15(6): 393
    Pyroptosis and mitochondrial function participated in miR-654-3p-protected against myocardial infarction.
    Chan Wu, Xiao-Cheng Zhang, Lan-Ruo Chen, Hui-Zhu Huang, Wei-Yin Wu, Yan Wang, Gang Li.
      Myocardial infarction (MI) is one of the leading causes of heart failure with highly complicated pathogeneses. miR-654-3p has been recognized as a pivotal regulator of controlling cell survival. However, the function of miR-654-3p in cardiomyocytes and MI has yet to be reported. This study aimed to identify the role of miR-654-3p in the regulation of myocardial infarction. To understand the contribution of miR-654-3p on heart function, we generated cardiac-specific knockdown and overexpression mice using AAV9 technology in MI injury. Mechanically, we combined cellular and molecular techniques, pharmaceutical treatment, RNA sequencing, and functional testing to elucidate the potential pathological mechanisms. We identified that mice subjected to MI decreased the expression of miR-654-3p in the border and infarcted area. Mice lacking miR-654-3p in the heart showed some inflammation infiltration and myocardial fibrosis, resulting in a mild cardiac injury. Furthermore, we found a deficiency of miR-654-3p in cardiomyocytes resulted in pyroptotic cell death but not other programmed cell death. Intriguingly, miR-654-3p deficiency aggravated MI-induced cardiac dysfunction, accompanied by higher myocardial fibrosis and cardiac enzymes and augmented pyroptosis activation. Cardiac elevating miR-654-3p prevented myocardial fibrosis and inflammation infiltration and decreased pyroptosis profile, thereby attenuating MI-induced cardiac damage. Using RNA sequence and molecular biological approaches, we found overexpression of miR-654-3p in the heart promoted the metabolic ability of the cardiomyocytes by promoting mitochondrial metabolism and mitochondrial respiration function. Our finding identified the character of miR-654-3p in protecting against MI damage by mediating pyroptosis and mitochondrial metabolism. These findings provide a new mechanism for miR-654-3p involvement in the pathogenesis of MI and reveal novel therapeutic targets. miR-654-3p expression was decreased after MI. Mice lacking miR-654-3p in the heart showed some inflammation infiltration and myocardial fibrosis, resulting in a mild cardiac injury. The deficiency of miR-654-3p in cardiomyocytes resulted in pyroptotic cell death. miR-654-3p deficiency aggravated MI-induced cardiac dysfunction, accompanied by higher myocardial fibrosis and cardiac enzymes and augmented pyroptosis activation. Overexpression of miR-654-3p prevented myocardial fibrosis and inflammation infiltration and decreased pyroptosis profile, thereby attenuating MI-induced cardiac damage. Overexpression of miR-654-3p in the heart promoted the metabolic ability of the cardiomyocytes by promoting mitochondrial metabolism and mitochondrial respiration function.
    DOI:  https://doi.org/10.1038/s41419-024-06786-4
  6. Circulation. 2024 Jun 06.
    LncRNA DCRT Protects Against Dilated Cardiomyopathy by Preventing NDUFS2 Alternative Splicing by Binding to PTBP1.
    Hengzhi Du, Yanru Zhao, Jianpei Wen, Beibei Dai, Guo Hu, Yufei Zhou, Zhongwei Yin, Nan Ding, Huaping Li, Jiahui Fan, Xiang Nie, Feng Wang, Qian Liu, Zheng Wen, Gang Xu, Dao Wen Wang, Chen Chen.
      BACKGROUND: Dilated cardiomyopathy is characterized by left ventricular dilation and continuous systolic dysfunction. Mitochondrial impairment is critical in dilated cardiomyopathy; however, the underlying mechanisms remain unclear. Here, we explored the cardioprotective role of a heart-enriched long noncoding RNA, the dilated cardiomyopathy repressive transcript (DCRT), in maintaining mitochondrial function.METHODS: The DCRT knockout (DCRT-/-) mice and DCRT knockout cells were developed using CRISPR-Cas9 technology. Cardiac-specific DCRT transgenic mice were generated using α-myosin heavy chain promoter. Chromatin coimmunoprecipitation, RNA immunoprecipitation, Western blot, and isoform sequencing were performed to investigate the underlying mechanisms.
    RESULTS: We found that the long noncoding RNA DCRT was highly enriched in the normal heart tissues and that its expression was significantly downregulated in the myocardium of patients with dilated cardiomyopathy. DCRT-/- mice spontaneously developed cardiac dysfunction and enlargement with mitochondrial impairment. DCRT transgene or overexpression with the recombinant adeno-associated virus system in mice attenuated cardiac dysfunction induced by transverse aortic constriction treatment. Mechanistically, DCRT inhibited the third exon skipping of NDUFS2 (NADH dehydrogenase ubiquinone iron-sulfur protein 2) by directly binding to PTBP1 (polypyrimidine tract binding protein 1) in the nucleus of cardiomyocytes. Skipping of the third exon of NDUFS2 induced mitochondrial dysfunction by competitively inhibiting mitochondrial complex I activity and binding to PRDX5 (peroxiredoxin 5) and suppressing its antioxidant activity. Furthermore, coenzyme Q10 partially alleviated mitochondrial dysfunction in cardiomyocytes caused by DCRT reduction.
    CONCLUSIONS: Our study revealed that the loss of DCRT contributed to PTBP1-mediated exon skipping of NDUFS2, thereby inducing cardiac mitochondrial dysfunction during dilated cardiomyopathy development, which could be partially treated with coenzyme Q10 supplementation.
    Keywords:  NDUFS2 protein, human; PTBP1 protein, human; RNA, long, noncoding; cardiomyopathy, dilated; exons; mitochondria
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.123.067861
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