bims-lypmec Biomed News
on Lysosomal positioning and metabolism in cardiomyocytes
Issue of 2023‒05‒28
eight papers selected by
Satoru Kobayashi
New York Institute of Technology
  1. Studying lysosomal function and dysfunction using LysoIP.
  2. Transmembrane Protein 175, a Lysosomal Ion Channel Related to Parkinson's Disease.
  3. Inhibition of endolysosome fusion increases exosome secretion.
  4. Integrated Control of Fatty Acid Metabolism in Heart Failure.
  5. Organelle Membrane Extensions in Mammalian Cells.
  6. Metabolic mechanisms in physiological and pathological cardiac hypertrophy: new paradigms and challenges.
  7. The role of lysosomal membrane proteins in autophagy and related diseases.
  8. Redefining the role of AMPK in autophagy and the energy stress response.
  1. Nat Rev Mol Cell Biol. 2023 May 26.
    Studying lysosomal function and dysfunction using LysoIP.
    Nouf N Laqtom.
      
    DOI:  https://doi.org/10.1038/s41580-023-00619-6
  2. Biomolecules. 2023 May 09. pii: 802. [Epub ahead of print]13(5):
    Transmembrane Protein 175, a Lysosomal Ion Channel Related to Parkinson's Disease.
    Tuoxian Tang, Boshuo Jian, Zhenjiang Liu.
      Lysosomes are membrane-bound organelles with an acidic lumen and are traditionally characterized as a recycling center in cells. Lysosomal ion channels are integral membrane proteins that form pores in lysosomal membranes and allow the influx and efflux of essential ions. Transmembrane protein 175 (TMEM175) is a unique lysosomal potassium channel that shares little sequence similarity with other potassium channels. It is found in bacteria, archaea, and animals. The prokaryotic TMEM175 consists of one six-transmembrane domain that adopts a tetrameric architecture, while the mammalian TMEM175 is comprised of two six-transmembrane domains that function as a dimer in lysosomal membranes. Previous studies have demonstrated that the lysosomal K+ conductance mediated by TMEM175 is critical for setting membrane potential, maintaining pH stability, and regulating lysosome-autophagosome fusion. AKT and B-cell lymphoma 2 regulate TMEM175's channel activity through direct binding. Two recent studies reported that the human TMEM175 is also a proton-selective channel under normal lysosomal pH (4.5-5.5) as the K+ permeation dramatically decreased at low pH while the H+ current through TMEM175 greatly increased. Genome-wide association studies and functional studies in mouse models have established that TMEM175 is implicated in the pathogenesis of Parkinson's disease, which sparks more research interests in this lysosomal channel.
    Keywords:  Parkinson’s disease; TMEM175; lysosome; potassium channel; proton channel
    DOI:  https://doi.org/10.3390/biom13050802
  3. J Cell Biol. 2023 06 05. pii: e202209084. [Epub ahead of print]222(6):
    Inhibition of endolysosome fusion increases exosome secretion.
    Ganesh Vilas Shelke, Chad D Williamson, Michal Jarnik, Juan S Bonifacino.
      Exosomes are small vesicles that are secreted from cells to dispose of undegraded materials and mediate intercellular communication. A major source of exosomes is intraluminal vesicles within multivesicular endosomes that undergo exocytic fusion with the plasma membrane. An alternative fate of multivesicular endosomes is fusion with lysosomes, resulting in degradation of the intraluminal vesicles. The factors that determine whether multivesicular endosomes fuse with the plasma membrane or with lysosomes are unknown. In this study, we show that impairment of endolysosomal fusion by disruption of a pathway involving the BLOC-one-related complex (BORC), the small GTPase ARL8, and the tethering factor HOPS increases exosome secretion by preventing the delivery of intraluminal vesicles to lysosomes. These findings demonstrate that endolysosomal fusion is a critical determinant of the amount of exosome secretion and suggest that suppression of the BORC-ARL8-HOPS pathway could be used to boost exosome yields in biotechnology applications.
    DOI:  https://doi.org/10.1083/jcb.202209084
  4. Metabolites. 2023 Apr 29. pii: 615. [Epub ahead of print]13(5):
    Integrated Control of Fatty Acid Metabolism in Heart Failure.
    Xiaoting Li, Xukun Bi.
      Disrupted fatty acid metabolism is one of the most important metabolic features in heart failure. The heart obtains energy from fatty acids via oxidation. However, heart failure results in markedly decreased fatty acid oxidation and is accompanied by the accumulation of excess lipid moieties that lead to cardiac lipotoxicity. Herein, we summarized and discussed the current understanding of the integrated regulation of fatty acid metabolism (including fatty acid uptake, lipogenesis, lipolysis, and fatty acid oxidation) in the pathogenesis of heart failure. The functions of many enzymes and regulatory factors in fatty acid homeostasis were characterized. We reviewed their contributions to the development of heart failure and highlighted potential targets that may serve as promising new therapeutic strategies.
    Keywords:  cardiac lipotoxicity; fatty acid homeostasis; heart failure
    DOI:  https://doi.org/10.3390/metabo13050615
  5. Biology (Basel). 2023 Apr 27. pii: 664. [Epub ahead of print]12(5):
    Organelle Membrane Extensions in Mammalian Cells.
    Ruth E Carmichael, David M Richards, H Dariush Fahimi, Michael Schrader.
      Organelles within eukaryotic cells are not isolated static compartments, instead being morphologically diverse and highly dynamic in order to respond to cellular needs and carry out their diverse and cooperative functions. One phenomenon exemplifying this plasticity, and increasingly gaining attention, is the extension and retraction of thin tubules from organelle membranes. While these protrusions have been observed in morphological studies for decades, their formation, properties and functions are only beginning to be understood. In this review, we provide an overview of what is known and still to be discovered about organelle membrane protrusions in mammalian cells, focusing on the best-characterised examples of these membrane extensions arising from peroxisomes (ubiquitous organelles involved in lipid metabolism and reactive oxygen species homeostasis) and mitochondria. We summarise the current knowledge on the diversity of peroxisomal/mitochondrial membrane extensions, as well as the molecular mechanisms by which they extend and retract, necessitating dynamic membrane remodelling, pulling forces and lipid flow. We also propose broad cellular functions for these membrane extensions in inter-organelle communication, organelle biogenesis, metabolism and protection, and finally present a mathematical model that suggests that extending protrusions is the most efficient way for an organelle to explore its surroundings.
    Keywords:  membrane dynamics; membrane protrusion; mitochondria; nanotubule; organelle interaction; organelles; peroxisomes
    DOI:  https://doi.org/10.3390/biology12050664
  6. Nat Rev Cardiol. 2023 May 26.
    Metabolic mechanisms in physiological and pathological cardiac hypertrophy: new paradigms and challenges.
    Julia Ritterhoff, Rong Tian.
      Cardiac metabolism is vital for heart function. Given that cardiac contraction requires a continuous supply of ATP in large quantities, the role of fuel metabolism in the heart has been mostly considered from the perspective of energy production. However, the consequence of metabolic remodelling in the failing heart is not limited to a compromised energy supply. The rewired metabolic network generates metabolites that can directly regulate signalling cascades, protein function, gene transcription and epigenetic modifications, thereby affecting the overall stress response of the heart. In addition, metabolic changes in both cardiomyocytes and non-cardiomyocytes contribute to the development of cardiac pathologies. In this Review, we first summarize how energy metabolism is altered in cardiac hypertrophy and heart failure of different aetiologies, followed by a discussion of emerging concepts in cardiac metabolic remodelling, that is, the non-energy-generating function of metabolism. We highlight challenges and open questions in these areas and finish with a brief perspective on how mechanistic research can be translated into therapies for heart failure.
    DOI:  https://doi.org/10.1038/s41569-023-00887-x
  7. FEBS J. 2023 May 23.
    The role of lysosomal membrane proteins in autophagy and related diseases.
    Jiahao Xu, Jing Gu, Wenjun Pei, Yao Zhang, Lizhuo Wang, Jialin Gao.
      As a self-degrading and highly conserved survival mechanism, autophagy plays an important role in maintaining cell survival and recycling. The discovery of autophagy-related (ATG) genes has revolutionized our understanding of autophagy. Lysosomal membrane proteins (LMPs) are important executors of lysosomal function, and increasing evidence has demonstrated their role in the induction and regulation of autophagy. In addition, the functional dysregulation of the process mediated by LMPs at all stages of autophagy is closely related to neurodegenerative diseases and cancer. Here, we review the role of LMPs in autophagy, focusing on their roles in vesicle nucleation, vesicle elongation and completion, the fusion of autophagosomes and lysosomes, and degradation, as well as their broad association with related diseases.
    Keywords:  Autophagy; Autophagy-related gene; Disease; Lysosomal membrane protein; Lysosome
    DOI:  https://doi.org/10.1111/febs.16820
  8. Nat Commun. 2023 May 24. 14(1): 2994
    Redefining the role of AMPK in autophagy and the energy stress response.
    Ji-Man Park, Da-Hye Lee, Do-Hyung Kim.
      Autophagy maintains cellular homeostasis during low energy states. According to the current understanding, glucose-depleted cells induce autophagy through AMPK, the primary energy-sensing kinase, to acquire energy for survival. However, contrary to the prevailing concept, our study demonstrates that AMPK inhibits ULK1, the kinase responsible for autophagy initiation, thereby suppressing autophagy. We found that glucose starvation suppresses amino acid starvation-induced stimulation of ULK1-Atg14-Vps34 signaling via AMPK activation. During an energy crisis caused by mitochondrial dysfunction, the LKB1-AMPK axis inhibits ULK1 activation and autophagy induction, even under amino acid starvation. Despite its inhibitory effect, AMPK protects the ULK1-associated autophagy machinery from caspase-mediated degradation during energy deficiency, preserving the cellular ability to initiate autophagy and restore homeostasis once the stress subsides. Our findings reveal that dual functions of AMPK, restraining abrupt induction of autophagy upon energy shortage while preserving essential autophagy components, are crucial to maintain cellular homeostasis and survival during energy stress.
    DOI:  https://doi.org/10.1038/s41467-023-38401-z
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