bims-lypmec Biomed News
on Lysosomal positioning and metabolism in cardiomyocytes
Issue of 2024‒02‒25
ten papers selected by
Satoru Kobayashi, New York Institute of Technology
  1. A SPLICS reporter reveals [Formula: see text]-synuclein regulation of lysosome-mitochondria contacts which affects TFEB nuclear translocation.
  2. TFEB activation triggers pexophagy for functional adaptation during oxidative stress under calcium deficient-conditions.
  3. Drosophila TMEM63 and mouse TMEM63A are lysosomal mechanosensory ion channels.
  4. ER remodeling via lipid metabolism.
  5. Lysosomal channels sensing forces.
  6. Redefining Diabetic Cardiomyopathy: Perturbations in Substrate Metabolism at the Heart of its Pathology.
  7. Sphingolipid metabolism controls mammalian heart regeneration.
  8. Regulation of cardiomyocyte intracellular trafficking and signal transduction by protein palmitoylation.
  9. Cardiomyocyte-specific deletion of GCN5L1 reduces lysine acetylation and attenuates diastolic dysfunction in aged mice by improving cardiac fatty acid oxidation.
  10. Post translational modifications of connexin 43 in ventricular arrhythmias after myocardial infarction.
  1. Nat Commun. 2024 Feb 19. 15(1): 1516
    A SPLICS reporter reveals [Formula: see text]-synuclein regulation of lysosome-mitochondria contacts which affects TFEB nuclear translocation.
    Flavia Giamogante, Lucia Barazzuol, Francesca Maiorca, Elena Poggio, Alessandra Esposito, Anna Masato, Gennaro Napolitano, Alessio Vagnoni, Tito Calì, Marisa Brini.
      Mitochondrial and lysosomal activities are crucial to maintain cellular homeostasis: optimal coordination is achieved at their membrane contact sites where distinct protein machineries regulate organelle network dynamics, ions and metabolites exchange. Here we describe a genetically encoded SPLICS reporter for short- and long- juxtapositions between mitochondria and lysosomes. We report the existence of narrow and wide lysosome-mitochondria contacts differently modulated by mitophagy, autophagy and genetic manipulation of tethering factors. The overexpression of α-synuclein (α-syn) reduces the apposition of mitochondria/lysosomes membranes and affects their privileged Ca2+ transfer, impinging on TFEB nuclear translocation. We observe enhanced TFEB nuclear translocation in α-syn-overexpressing cells. We propose that α-syn, by interfering with mitochondria/lysosomes tethering impacts on local Ca2+ regulated pathways, among which TFEB mediated signaling, and in turn mitochondrial and lysosomal function. Defects in mitochondria and lysosome represent a common hallmark of neurodegenerative diseases: targeting their communication could open therapeutic avenues.
    DOI:  https://doi.org/10.1038/s41467-024-46007-2
  2. Cell Commun Signal. 2024 Feb 21. 22(1): 142
    TFEB activation triggers pexophagy for functional adaptation during oxidative stress under calcium deficient-conditions.
    Laxman Manandhar, Raghbendra Kumar Dutta, Pradeep Devkota, Arun Chhetri, Xiaofan Wei, Channy Park, Hyug Moo Kwon, Raekil Park.
      BACKGROUND: Calcium is a ubiquitous intracellular messenger that regulates the expression of various genes involved in cell proliferation, differentiation, and motility. The involvement of calcium in diverse metabolic pathways has been suggested. However, the effect of calcium in peroxisomes, which are involved in fatty acid oxidation and scavenges the result reactive oxygen species (ROS), remains elusive. In addition, impaired peroxisomal ROS inhibit the mammalian target of rapamycin complex 1 (mTORC1) and promote autophagy. Under stress, autophagy serves as a protective mechanism to avoid cell death. In response to oxidative stress, lysosomal calcium mediates transcription factor EB (TFEB) activation. However, the impact of calcium on peroxisome function and the mechanisms governing cellular homeostasis to prevent diseases caused by calcium deficiency are currently unknown.METHODS: To investigate the significance of calcium in peroxisomes and their roles in preserving cellular homeostasis, we established an in-vitro scenario of calcium depletion.
    RESULTS: This study demonstrated that calcium deficiency reduces catalase activity, resulting in increased ROS accumulation in peroxisomes. This, in turn, inhibits mTORC1 and induces pexophagy through TFEB activation. However, treatment with the antioxidant N-acetyl-l-cysteine (NAC) and the autophagy inhibitor chloroquine impeded the nuclear translocation of TFEB and attenuated peroxisome degradation.
    CONCLUSIONS: Collectively, our study revealed that ROS-mediated TFEB activation triggers pexophagy during calcium deficiency, primarily because of attenuated catalase activity. We posit that calcium plays a significant role in the proper functioning of peroxisomes, critical for fatty-acid oxidation and ROS scavenging in maintaining cellular homeostasis. These findings have important implications for signaling mechanisms in various pathologies, including Zellweger's syndrome and ageing.
    Keywords:  Autophagy; Calcium; Catalase; Peroxisome; ROS; TFEB
    DOI:  https://doi.org/10.1186/s12964-024-01524-x
  3. Nat Cell Biol. 2024 Feb 22.
    Drosophila TMEM63 and mouse TMEM63A are lysosomal mechanosensory ion channels.
    Kai Li, Yanmeng Guo, Yayu Wang, Ruijun Zhu, Wei Chen, Tong Cheng, Xiaofan Zhang, Yinjun Jia, Ting Liu, Wei Zhang, Lily Yeh Jan, Yuh Nung Jan.
      Cells sense physical forces and convert them into electrical or chemical signals, a process known as mechanotransduction. Whereas extensive studies focus on mechanotransduction at the plasma membrane, little is known about whether and how intracellular organelles sense mechanical force and the physiological functions of organellar mechanosensing. Here we identify the Drosophila TMEM63 (DmTMEM63) ion channel as an intrinsic mechanosensor of the lysosome, a major degradative organelle. Endogenous DmTMEM63 proteins localize to lysosomes, mediate lysosomal mechanosensitivity and modulate lysosomal morphology and function. Tmem63 mutant flies exhibit impaired lysosomal degradation, synaptic loss, progressive motor deficits and early death, with some of these mutant phenotypes recapitulating symptoms of TMEM63-associated human diseases. Importantly, mouse TMEM63A mediates lysosomal mechanosensitivity in Neuro-2a cells, indicative of functional conservation in mammals. Our findings reveal DmTMEM63 channel function in lysosomes and its physiological roles in vivo and provide a molecular basis to explore the mechanosensitive process in subcellular organelles.
    DOI:  https://doi.org/10.1038/s41556-024-01353-7
  4. Trends Cell Biol. 2024 Feb 22. pii: S0962-8924(24)00023-0. [Epub ahead of print]
    ER remodeling via lipid metabolism.
    Wonyul Jang, Volker Haucke.
      Unlike most other organelles found in multiple copies, the endoplasmic reticulum (ER) is a unique singular organelle within eukaryotic cells. Despite its continuous membrane structure, encompassing more than half of the cellular endomembrane system, the ER is subdivided into specialized sub-compartments, including morphological, membrane contact site (MCS), and de novo organelle biogenesis domains. In this review, we discuss recent emerging evidence indicating that, in response to nutrient stress, cells undergo a reorganization of these sub-compartmental ER domains through two main mechanisms: non-destructive remodeling of morphological ER domains via regulation of MCS and organelle hitchhiking, and destructive remodeling of specialized domains by ER-phagy. We further highlight and propose a critical role of membrane lipid metabolism in this ER remodeling during starvation.
    Keywords:  endoplasmic reticulum; hitchhiking; lipids; membrane contact sites; membrane remodeling; metabolism; nutrient stress
    DOI:  https://doi.org/10.1016/j.tcb.2024.01.011
  5. Nat Cell Biol. 2024 Feb 22.
    Lysosomal channels sensing forces.
    Erika Riederer, Dejian Ren.
      
    DOI:  https://doi.org/10.1038/s41556-024-01347-5
  6. Diabetes. 2024 Feb 22. pii: dbi230019. [Epub ahead of print]
    Redefining Diabetic Cardiomyopathy: Perturbations in Substrate Metabolism at the Heart of its Pathology.
    Lisa C Heather, Keshav Gopal, Nikola Srnic, John R Ussher.
      Cardiovascular disease represents the leading cause of death in people with diabetes, most notably from macrovascular diseases such as myocardial infarction or heart failure. Diabetes also increases the risk of a specific form of cardiomyopathy referred to as diabetic cardiomyopathy (DbCM), originally defined as ventricular dysfunction in the absence of underlying coronary artery disease and/or hypertension. Herein, we provide an overview on the key mediators of DbCM, with an emphasis on the role for perturbations in cardiac substrate metabolism. We discuss key mechanisms regulating metabolic dysfunction in DbCM, with additional focus on the role of metabolites as signalling molecules within the diabetic heart. Furthermore, we discuss the preclinical approaches to target these perturbations to alleviate DbCM. With several advancements in our understanding, we propose "diastolic dysfunction in the presence of altered myocardial metabolism in a person with diabetes, but absence of other known causes of cardiomyopathy and/or hypertension", as a new definition for, or approach to classify, DbCM. However, we recognize that no definition can fully explain the complexity of why some individuals with DbCM exhibit diastolic dysfunction, whereas others develop systolic dysfunction. Due to DbCM sharing pathological features with heart failure with preserved ejection fraction (HFpEF), the latter of which is more prevalent in the diabetic population, it is imperative to determine whether effective management of DbCM decreases HFpEF prevalence.
    DOI:  https://doi.org/10.2337/dbi23-0019
  7. Cell Metab. 2024 Feb 07. pii: S1550-4131(24)00017-2. [Epub ahead of print]
    Sphingolipid metabolism controls mammalian heart regeneration.
    Xiaoqian Ji, Zihao Chen, Qiyuan Wang, Bin Li, Yan Wei, Yun Li, Jianqing Lin, Weisheng Cheng, Yijie Guo, Shilin Wu, Longkun Mao, Yuzhou Xiang, Tian Lan, Shanshan Gu, Meng Wei, Joe Z Zhang, Lan Jiang, Jia Wang, Jin Xu, Nan Cao.
      Utilization of lipids as energy substrates after birth causes cardiomyocyte (CM) cell-cycle arrest and loss of regenerative capacity in mammalian hearts. Beyond energy provision, proper management of lipid composition is crucial for cellular and organismal health, but its role in heart regeneration remains unclear. Here, we demonstrate widespread sphingolipid metabolism remodeling in neonatal hearts after injury and find that SphK1 and SphK2, isoenzymes producing the same sphingolipid metabolite sphingosine-1-phosphate (S1P), differently regulate cardiac regeneration. SphK2 is downregulated during heart development and determines CM proliferation via nuclear S1P-dependent modulation of histone acetylation. Reactivation of SphK2 induces adult CM cell-cycle re-entry and cytokinesis, thereby enhancing regeneration. Conversely, SphK1 is upregulated during development and promotes fibrosis through an S1P autocrine mechanism in cardiac fibroblasts. By fine-tuning the activity of each SphK isoform, we develop a therapy that simultaneously promotes myocardial repair and restricts fibrotic scarring to regenerate the infarcted adult hearts.
    Keywords:  SphK1; SphK2; cardiac fibrosis; cardiomyocyte proliferation; heart regeneration; sphingolipid metabolism
    DOI:  https://doi.org/10.1016/j.cmet.2024.01.017
  8. Biochem Soc Trans. 2024 Feb 22. pii: BST20221296. [Epub ahead of print]
    Regulation of cardiomyocyte intracellular trafficking and signal transduction by protein palmitoylation.
    Kobina Essandoh, James P Teuber, Matthew J Brody.
      Despite the well-established functions of protein palmitoylation in fundamental cellular processes, the roles of this reversible post-translational lipid modification in cardiomyocyte biology remain poorly studied. Palmitoylation is catalyzed by a family of 23 zinc finger and Asp-His-His-Cys domain-containing S-acyltransferases (zDHHC enzymes) and removed by select thioesterases of the lysophospholipase and α/β-hydroxylase domain (ABHD)-containing families of serine hydrolases. Recently, studies utilizing genetic manipulation of zDHHC enzymes in cardiomyocytes have begun to unveil essential functions for these enzymes in regulating cardiac development, homeostasis, and pathogenesis. Palmitoylation co-ordinates cardiac electrophysiology through direct modulation of ion channels and transporters to impact their trafficking or gating properties as well as indirectly through modification of regulators of channels, transporters, and calcium handling machinery. Not surprisingly, palmitoylation has roles in orchestrating the intracellular trafficking of proteins in cardiomyocytes, but also dynamically fine-tunes cardiomyocyte exocytosis and natriuretic peptide secretion. Palmitoylation has emerged as a potent regulator of intracellular signaling in cardiomyocytes, with recent studies uncovering palmitoylation-dependent regulation of small GTPases through direct modification and sarcolemmal targeting of the small GTPases themselves or by modification of regulators of the GTPase cycle. In addition to dynamic control of G protein signaling, cytosolic DNA is sensed and transduced into an inflammatory transcriptional output through palmitoylation-dependent activation of the cGAS-STING pathway, which has been targeted pharmacologically in preclinical models of heart disease. Further research is needed to fully understand the complex regulatory mechanisms governed by protein palmitoylation in cardiomyocytes and potential emerging therapeutic targets.
    Keywords:  S-acylation; cardiomyocyte; exocytosis; intracellular signaling; palmitoylation; trafficking
    DOI:  https://doi.org/10.1042/BST20221296
  9. Biochem J. 2024 Feb 23. pii: BCJ20230421. [Epub ahead of print]
    Cardiomyocyte-specific deletion of GCN5L1 reduces lysine acetylation and attenuates diastolic dysfunction in aged mice by improving cardiac fatty acid oxidation.
    Jackson E Stewart, Jenna M Crawford, William E Mullen, Angelica Jacques, Michael W Stoner, Iain Scott, Dharendra Thapa.
      Cardiac mitochondrial dysfunction is a critical contributor to the pathogenesis of aging and many age-related conditions. As such, complete control of mitochondrial function is critical to maintain cardiac efficiency in the aged heart. Lysine acetylation is a reversible post-translational modification shown to regulate several mitochondrial metabolic and biochemical processes. In the present study, we investigated how mitochondrial lysine acetylation regulates fatty acid oxidation and cardiac function in the aged heart. We found a significant increase in mitochondrial protein acetylation in the aged heart which correlated with increased level of mitochondrial acetyltransferase-related protein GCN5L1. We showed that acetylation status of several fatty acid and glucose oxidation enzymes (long-chain acyl-CoA dehydrogenase, hydroxyacyl-coA dehydrogenase, and pyruvate dehydrogenase) were significantly upregulated in aged heart which correlated with decreased enzymatic activities. Using a cardiac-specific GCN5L1 knockout animal model, we showed that overall acetylation of mitochondrial proteins was decreased in aged knockout animals, including fatty acid oxidation proteins which led to improved fatty acid oxidation activity and attenuated cardiac diastolic dysfunction observed in the aged heart. Together, these findings indicate that lysine acetylation regulates fatty acid oxidation in the aged heart which results in improved cardiac diastolic function and this is in part regulated by GCN5L1.
    Keywords:  aging; cardiac function; fatty acid oxidation; lysine acetylation; mitochondria
    DOI:  https://doi.org/10.1042/BCJ20230421
  10. Mol Biol Rep. 2024 Feb 23. 51(1): 329
    Post translational modifications of connexin 43 in ventricular arrhythmias after myocardial infarction.
    Fan Yang, Xiao-Lu Zhang, Huan-Huan Liu, Ling-Ling Qian, Ru-Xing Wang.
      Ventricular arrhythmias are the leading cause of sudden cardiac death in patients after myocardial infarction (MI). Connexin43 (Cx43) is the most important gap junction channel-forming protein in cardiomyocytes. Dysfunction of Cx43 contributes to impaired myocardial conduction and the development of ventricular arrhythmias. Following an MI, Cx43 undergoes structural remodeling, including expression abnormalities, and redistribution. These alterations detrimentally affect intercellular communication and electrical conduction within the myocardium, thereby increasing the susceptibility to post-infarction ventricular arrhythmias. Emerging evidence suggests that post-translational modifications play essential roles in Cx43 regulation after MI. Therefore, Cx43-targeted management has the potential to be a promising protective strategy for the prevention and treatment of post infarction ventricular arrhythmias. In this article, we primarily reviewed the regulatory mechanisms of Cx43 mediated post-translational modifications on post-infarction ventricular arrhythmias. Furthermore, Cx43-targeted therapy have also been discussed, providing insights into an innovative treatment strategy for ventricular arrhythmias after MI.
    Keywords:  Cardiomyocyte; Connexin43; Myocardial infarction; Post translational modifications; Ventricular arrhythmias
    DOI:  https://doi.org/10.1007/s11033-024-09290-2
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