bims-lypmec Biomed News
on Lysosomal positioning and metabolism in cardiomyocytes
Issue of 2023‒01‒15
ten papers selected by
Satoru Kobayashi
New York Institute of Technology
  1. GATOR2 rings GATOR1 to speak to mTORC1.
  2. Consecutive functions of small GTPases guide HOPS-mediated tethering of late endosomes and lysosomes.
  3. SLC7A14 imports GABA to lysosomes and impairs hepatic insulin sensitivity via inhibiting mTORC2.
  4. Glutamine Produces Ammonium to Tune Lysosomal pH and Regulate Lysosomal Function.
  5. LYSET/TMEM251/GCAF is critical for autophagy and lysosomal function by regulating the mannose-6-phosphate (M6P) pathway.
  6. LYSET/TMEM251- a novel key component of the mannose-6-phosphate pathway.
  7. Dual-response and lysosome-targeted fluorescent probe for viscosity and sulfur dioxide derivatives.
  8. GTP energy dependence of endocytosis and autophagy in the aging brain and Alzheimer's disease.
  9. SGLT2 inhibitors: role in protective reprogramming of cardiac nutrient transport and metabolism.
  10. Metabolites as signalling molecules.
  1. Mol Cell. 2023 Jan 05. pii: S1097-2765(22)01168-6. [Epub ahead of print]83(1): 6-8
    GATOR2 rings GATOR1 to speak to mTORC1.
    Umakant Sahu, Issam Ben-Sahra.
      The mechanistic target of rapamycin complex 1 (mTORC1) senses cellular leucine levels through the GATOR1/2-Rag axis. Jiang et al. show that the Ring domains of GATOR2 subunits maintain the integrity of the complex and promote ubiquitination and inhibition of GATOR1, thereby leading to mTORC1 activation.
    DOI:  https://doi.org/10.1016/j.molcel.2022.12.011
  2. Cell Rep. 2023 Jan 04. pii: S2211-1247(22)01873-3. [Epub ahead of print]42(1): 111969
    Consecutive functions of small GTPases guide HOPS-mediated tethering of late endosomes and lysosomes.
    Ariane Schleinitz, Lara-Alina Pöttgen, Tal Keren-Kaplan, Jing Pu, Paul Saftig, Juan S Bonifacino, Albert Haas, Andreas Jeschke.
      The transfer of endocytosed cargoes to lysosomes (LYSs) requires HOPS, a multiprotein complex that tethers late endosomes (LEs) to LYSs before fusion. Many proteins interact with HOPS on LEs/LYSs. However, it is not clear whether these HOPS interactors localize to LEs or LYSs or how they participate in tethering. Here, we biochemically characterized endosomes purified from untreated or experimentally manipulated cells to put HOPS and interacting proteins in order and to establish their functional interdependence. Our results assign Rab2a and Rab7 to LEs and Arl8 and BORC to LYSs and show that HOPS drives LE-LYS fusion by bridging late endosomal Rab2a with lysosomal BORC-anchored Arl8. We further show that Rab7 is absent from sites of HOPS-dependent tethering but promotes fusion by moving LEs toward LYSs via dynein. Thus, our study identifies the topology of the machinery for LE-LYS tethering and elucidates the role of different small GTPases in the process.
    Keywords:  CP: Cell biology; autophagosome; autophagy; dynein; endolysosome; lysosome reformation; membrane fusion; membrane tethering; phagocytosis; phosphoinositides; protein trafficking
    DOI:  https://doi.org/10.1016/j.celrep.2022.111969
  3. Cell Rep. 2023 Jan 10. pii: S2211-1247(22)01888-5. [Epub ahead of print]42(1): 111984
    SLC7A14 imports GABA to lysosomes and impairs hepatic insulin sensitivity via inhibiting mTORC2.
    Xiaoxue Jiang, Kan Liu, Haizhou Jiang, Hanrui Yin, En-Duo Wang, Hong Cheng, Feixiang Yuan, Fei Xiao, Fenfen Wang, Wei Lu, Bo Peng, Yousheng Shu, Xiaoying Li, Shanghai Chen, Feifan Guo.
      Lysosomal amino acid accumulation is implicated in several diseases, but its role in insulin resistance, the central mechanism to type 2 diabetes and many metabolic diseases, is unclear. In this study, we show the hepatic expression of lysosomal membrane protein solute carrier family 7 member 14 (SLC7A14) is increased in insulin-resistant mice. The promoting effect of SLC7A14 on insulin resistance is demonstrated by loss- and gain-of-function experiments. SLC7A14 is further demonstrated as a transporter resulting in the accumulation of lysosomal γ-aminobutyric acid (GABA), which induces insulin resistance via inhibiting mTOR complex 2 (mTORC2)'s activity. These results establish a causal link between lysosomal amino acids and insulin resistance and suggest that SLC7A14 inhibition may provide a therapeutic strategy in treating insulin resistance-related and GABA-related diseases and may provide insights into the upstream mechanisms for mTORC2, the master regulator in many important processes.
    Keywords:  CP: Metabolism; GABA; SLC7A14; amino acid; insulin resistance; liver; lysosome
    DOI:  https://doi.org/10.1016/j.celrep.2022.111984
  4. Cells. 2022 Dec 24. pii: 80. [Epub ahead of print]12(1):
    Glutamine Produces Ammonium to Tune Lysosomal pH and Regulate Lysosomal Function.
    Jian Xiong, Thi Thu Trang Luu, Kartik Venkatachalam, Guangwei Du, Michael X Zhu.
      Glutamine is one of the most abundant amino acids in the cell. In mitochondria, glutaminases 1 and 2 (GLS1/2) hydrolyze glutamine to glutamate, which serves as the precursor of multiple metabolites. Here, we show that ammonium generated during GLS1/2-mediated glutaminolysis regulates lysosomal pH and in turn lysosomal degradation. In primary human skin fibroblasts BJ cells and mouse embryonic fibroblasts, deprivation of total amino acids for 1 h increased lysosomal degradation capacity as shown by the increased turnover of lipidated microtubule-associated proteins 1A/1B light chain 3B (LC3-II), several autophagic receptors, and endocytosed DQ-BSA. Removal of glutamine but not any other amino acids from the culture medium enhanced lysosomal degradation similarly as total amino acid starvation. The presence of glutamine in regular culture media increased lysosomal pH by >0.5 pH unit and the removal of glutamine caused lysosomal acidification. GLS1/2 knockdown, GLS1 antagonist, or ammonium scavengers reduced lysosomal pH in the presence of glutamine. The addition of glutamine or NH4Cl prevented the increase in lysosomal degradation and curtailed the extension of mTORC1 function during the early time period of amino acid starvation. Our findings suggest that glutamine tunes lysosomal pH by producing ammonium, which regulates lysosomal degradation to meet the demands of cellular activities. During the early stage of amino acid starvation, the glutamine-dependent mechanism allows more efficient use of internal reserves and endocytosed proteins to extend mTORC1 activation such that the normal anabolism is not easily interrupted by a brief disruption of the amino acid supply.
    Keywords:  amino acid starvation; autophagosome; autophagy; glutaminase; glutamine; lysosomal pH; mTORC1 activation
    DOI:  https://doi.org/10.3390/cells12010080
  5. Autophagy. 2023 Jan 12.
    LYSET/TMEM251/GCAF is critical for autophagy and lysosomal function by regulating the mannose-6-phosphate (M6P) pathway.
    Bokai Zhang, Xi Yang, Ming Li.
      Vertebrate cells rely on mannose-6-phosphate (M6P) modifications to deliver most lumenal hydrolases to the lysosome. As a critical trafficking signal for lysosomal enzymes, the M6P biosynthetic pathway has been thoroughly investigated. However, its regulatory mechanism is largely unknown. Here, we summarize three recent studies that independently discovered LYSET/TMEM251/GCAF as a key regulator of the M6P pathway. LYSET/TMEM251 directly interacts with GNPT, the enzyme that catalyzes the transfer of M6P, and is critical for its activity and stability. Deleting LYSET/TMEM251 impairs the GNPT function and M6P modifications. Consequently, lysosomal enzymes are mistargeted for secretion. Defective lysosomes fail to degrade cargoes such as endocytic vesicles and autophagosomes, leading to a newly identified lysosomal storage disease in humans. These discoveries open up a new direction in the regulation of the M6P biosynthetic pathway.
    Keywords:  Autophagy; GNPT; M6P; TMEM251; lysosomal enzymes; lysosomal storage disease
    DOI:  https://doi.org/10.1080/15548627.2023.2167375
  6. Autophagy. 2023 Jan 12.
    LYSET/TMEM251- a novel key component of the mannose-6-phosphate pathway.
    Wenjie Qiao, Christopher M Richards, Sabrina Jabs.
      ​​Degradation of macromolecules delivered to lysosomes by processes such as autophagy or endocytosis is crucial for cellular function. Lysosomes require more than 60 soluble hydrolases in order to catabolize such macromolecules. These soluble hydrolases are tagged with mannose-6-phosphate (M6P) moieties in sequential reactions by the Golgi-resident GlcNAc-1-phosphotransferase complex and NAGPA/UCE/uncovering enzyme (N-acetylglucosamine-1-phosphodiester alpha-N-acetylglucosaminidase), which allows their delivery to endosomal/lysosomal compartments through trafficking mediated by cation-dependent and -independent mannose-6-phosphate receptors (MPRs). We and others recently identified TMEM251 as a novel regulator of the M6P pathway via independent genome-wide genetic screening strategies. We renamed TMEM251 to LYSET (lysosomal enzyme trafficking factor) to establish nomenclature reflective to this gene's function. LYSET is a Golgi-localized transmembrane protein important for the retention of the GlcNAc-1-phosphotransferase complex in the Golgi-apparatus. The current understanding of LYSET's importance regarding human biology is 3-fold: 1) highly pathogenic viruses that depend on lysosomal hydrolase activity require LYSET for infection. 2) The presence of LYSET is critical for cancer cell proliferation in nutrient-deprived environments in which extracellular proteins must be catabolized. 3) Inherited pathogenic alleles of LYSET can cause a severe inherited disease which resembles GlcNAc-1-phosphotransferase deficiency (i.e., mucolipidosis type II).
    Keywords:  GlcNAc-1-phosphotransferase; Golgi-apparatus; lysosomal enzyme trafficking; lysosome; mannose-6-phosphate; mucolipidosis type II
    DOI:  https://doi.org/10.1080/15548627.2023.2167376
  7. Anal Chim Acta. 2023 Jan 25. pii: S0003-2670(22)01292-2. [Epub ahead of print]1239 340721
    Dual-response and lysosome-targeted fluorescent probe for viscosity and sulfur dioxide derivatives.
    Feng Li, Bang-Zhao Zhou, Wen Yao, Shou-Kang Sun, Jun-Ying Miao, Bao-Xiang Zhao, Zhao-Min Lin.
      Viscosity and sulfur dioxide levels are important factors to evaluate the changes of cell micro-environment because a series of diseases usually occur when they are abnormal. At present, dual-response probes that can detect both viscosity and sulfur dioxide are rare. Therefore, we developed a novel fluorescent probe CBN for simultaneous detection of sulfur dioxide and viscosity. Besides, probe CBN could target lysosome of which normal function will be disrupted by the abnormality of viscosity. Therefore, probe CBN has the potential to be served as an effective biological tool to monitor the intracellular micro-environment.
    Keywords:  Cell imaging; Fluorescent probe; Lysosome; Sulfur dioxide derivatives; Viscosity
    DOI:  https://doi.org/10.1016/j.aca.2022.340721
  8. Geroscience. 2023 Jan 09.
    GTP energy dependence of endocytosis and autophagy in the aging brain and Alzheimer's disease.
    Ricardo A Santana Martínez, Priyanka D Pinky, Benjamin A Harlan, Gregory J Brewer.
      Increased interest in the aging and Alzheimer's disease (AD)-related impairments in autophagy in the brain raise important questions about regulation and treatment. Since many steps in endocytosis and autophagy depend on GTPases, new measures of cellular GTP levels are needed to evaluate energy regulation in aging and AD. The recent development of ratiometric GTP sensors (GEVALS) and findings that GTP levels are not homogenous inside cells raise new issues of regulation of GTPases by the local availability of GTP. In this review, we highlight the metabolism of GTP in relation to the Rab GTPases involved in formation of early endosomes, late endosomes, and lysosomal transport to execute the autophagic degradation of damaged cargo. Specific GTPases control macroautophagy (mitophagy), microautophagy, and chaperone-mediated autophagy (CMA). By inference, local GTP levels would control autophagy, if not in excess. Additional levels of control are imposed by the redox state of the cell, including thioredoxin involvement. Throughout this review, we emphasize the age-related changes that could contribute to deficits in GTP and AD. We conclude with prospects for boosting GTP levels and reversing age-related oxidative redox shift to restore autophagy. Therefore, GTP levels could regulate the numerous GTPases involved in endocytosis, autophagy, and vesicular trafficking. In aging, metabolic adaptation to a sedentary lifestyle could impair mitochondrial function generating less GTP and redox energy for healthy management of amyloid and tau proteostasis, synaptic function, and inflammation.
    Keywords:  Aging; Alzheimer’s; Autophagy; Endocytosis; Energetics; GTP; Lysosomes; Mitophagy
    DOI:  https://doi.org/10.1007/s11357-022-00717-x
  9. Nat Rev Cardiol. 2023 Jan 06.
    SGLT2 inhibitors: role in protective reprogramming of cardiac nutrient transport and metabolism.
    Milton Packer.
      Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce heart failure events by direct action on the failing heart that is independent of changes in renal tubular function. In the failing heart, nutrient transport into cardiomyocytes is increased, but nutrient utilization is impaired, leading to deficient ATP production and the cytosolic accumulation of deleterious glucose and lipid by-products. These by-products trigger downregulation of cytoprotective nutrient-deprivation pathways, thereby promoting cellular stress and undermining cellular survival. SGLT2 inhibitors restore cellular homeostasis through three complementary mechanisms: they might bind directly to nutrient-deprivation and nutrient-surplus sensors to promote their cytoprotective actions; they can increase the synthesis of ATP by promoting mitochondrial health (mediated by increasing autophagic flux) and potentially by alleviating the cytosolic deficiency in ferrous iron; and they might directly inhibit glucose transporter type 1, thereby diminishing the cytosolic accumulation of toxic metabolic by-products and promoting the oxidation of long-chain fatty acids. The increase in autophagic flux mediated by SGLT2 inhibitors also promotes the clearance of harmful glucose and lipid by-products and the disposal of dysfunctional mitochondria, allowing for mitochondrial renewal through mitochondrial biogenesis. This Review describes the orchestrated interplay between nutrient transport and metabolism and nutrient-deprivation and nutrient-surplus signalling, to explain how SGLT2 inhibitors reverse the profound nutrient, metabolic and cellular abnormalities observed in heart failure, thereby restoring the myocardium to a healthy molecular and cellular phenotype.
    DOI:  https://doi.org/10.1038/s41569-022-00824-4
  10. Nat Rev Mol Cell Biol. 2023 Jan 12.
    Metabolites as signalling molecules.
    Steven Andrew Baker, Jared Rutter.
      Traditional views of cellular metabolism imply that it is passively adapted to meet the demands of the cell. It is becoming increasingly clear, however, that metabolites do more than simply supply the substrates for biological processes; they also provide critical signals, either through effects on metabolic pathways or via modulation of other regulatory proteins. Recent investigation has also uncovered novel roles for several metabolites that expand their signalling influence to processes outside metabolism, including nutrient sensing and storage, embryonic development, cell survival and differentiation, and immune activation and cytokine secretion. Together, these studies suggest that, in contrast to the prevailing notion, the biochemistry of a cell is frequently governed by its underlying metabolism rather than vice versa. This important shift in perspective places common metabolites as key regulators of cell phenotype and behaviour. Yet the signalling metabolites, and the cognate targets and transducers through which they signal, are only beginning to be uncovered. In this Review, we discuss the emerging links between metabolism and cellular behaviour. We hope this will inspire further dissection of the mechanisms through which metabolic pathways and intermediates modulate cell function and will suggest possible drug targets for diseases linked to metabolic deregulation.
    DOI:  https://doi.org/10.1038/s41580-022-00572-w
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