bims-lypmec 2022-10-30 papers

Issue of 2022‒10‒30
seven papers selected by
Satoru Kobayashi
New York Institute of Technology

Open Biol. 2022 Oct;12(10): 220155

Lysosomal positioning diseases: beyond substrate storage.

Gianluca Scerra, Valeria De Pasquale, Melania Scarcella, Maria Gabriella Caporaso, Luigi Michele Pavone, Massimo D'Agostino.

Lysosomal storage diseases (LSDs) comprise a group of inherited monogenic disorders characterized by lysosomal dysfunctions due to undegraded substrate accumulation. They are caused by a deficiency in specific lysosomal hydrolases involved in cellular catabolism, or non-enzymatic proteins essential for normal lysosomal functions. In LSDs, the lack of degradation of the accumulated substrate and its lysosomal storage impairs lysosome functions resulting in the perturbation of cellular homeostasis and, in turn, the damage of multiple organ systems. A substantial number of studies on the pathogenesis of LSDs has highlighted how the accumulation of lysosomal substrates is only the first event of a cascade of processes including the accumulation of secondary metabolites and the impairment of cellular trafficking, cell signalling, autophagic flux, mitochondria functionality and calcium homeostasis, that significantly contribute to the onset and progression of these diseases. Emerging studies on lysosomal biology have described the fundamental roles of these organelles in a variety of physiological functions and pathological conditions beyond their canonical activity in cellular waste clearance. Here, we discuss recent advances in the knowledge of cellular and molecular mechanisms linking lysosomal positioning and trafficking to LSDs.

Keywords: lysosomal storage diseases; lysosome; membrane contact sites; microtubule tracks; positioning; trafficking

DOI: https://doi.org/10.1098/rsob.220155

Biology (Basel). 2022 Sep 27. pii: 1410. [Epub ahead of print]11(10):

Lysosomes and Their Role in Regulating the Metabolism of Hematopoietic Stem Cells.

Tasleem Arif.

Hematopoietic stem cells (HSCs) have the capacity to renew blood cells at all stages of life and are largely quiescent at a steady state. It is essential to understand the processes that govern quiescence in HSCs to enhance bone marrow transplantation. It is hypothesized that in their quiescent state, HSCs primarily use glycolysis for energy production rather than mitochondrial oxidative phosphorylation (OXPHOS). In addition, the HSC switch from quiescence to activation occurs along a continuous developmental path that is driven by metabolism. Specifying the metabolic regulation pathway of HSC quiescence will provide insights into HSC homeostasis for therapeutic application. Therefore, understanding the metabolic demands of HSCs at a steady state is key to developing innovative hematological therapeutics. Lysosomes are the major degradative organelle in eukaryotic cells. Catabolic, anabolic, and lysosomal function abnormalities are connected to an expanding list of diseases. In recent years, lysosomes have emerged as control centers of cellular metabolism, particularly in HSC quiescence, and essential regulators of cell signaling have been found on the lysosomal membrane. In addition to autophagic processes, lysosomal activities have been shown to be crucial in sustaining quiescence by restricting HSCs access to a nutritional reserve essential for their activation into the cell cycle. Lysosomal activity may preserve HSC quiescence by altering glycolysis-mitochondrial biogenesis. The understanding of HSC metabolism has significantly expanded over the decade, revealing previously unknown requirements of HSCs in both their dividing (active) and quiescent states. Therefore, understanding the role of lysosomes in HSCs will allow for the development of innovative treatment methods based on HSCs to fight clonal hematopoiesis and HSC aging.

Keywords: HSCs; glycolysis; lysosomes; metabolism; mitochondria; quiescence

DOI: https://doi.org/10.3390/biology11101410

J Diabetes Investig. 2022 Oct 28.

New mechanism of metformin action mediated by lysosomal presenilin enhancer 2.

Kenji Sugawara, Wataru Ogawa.

Formation of the PEN2-ATP6AP1 complex induced by the binding of metformin to PEN2 results in the inhibition of v-ATPase activity and in the recruitment of AXIN/LKB1 to lysosomes, which in turn results in the phosphorylation and activation of AMPK.

DOI: https://doi.org/10.1111/jdi.13925

Dev Cell. 2022 Oct 24. pii: S1534-5807(22)00684-0. [Epub ahead of print]57(20): 2347-2349

PITTching in for lysosome repair.

Claire S Goul, Roberto Zoncu.

Lysosomes, guardians of cell health, can sustain physical damage from biological, mechanical, and chemical stressors, necessitating dedicated mechanisms for their upkeep. In a recent issue of Nature, Tan and Finkel report the discovery of a lysosomal repair pathway controlled by phosphoinositides, which operates via bulk transport of lipids across ER-lysosome contacts.

DOI: https://doi.org/10.1016/j.devcel.2022.09.014

Mol Med Rep. 2022 Dec;pii: 368. [Epub ahead of print]26(6):

Multi‑faceted roles of cathepsins in ischemia reperfusion injury (Review).

Jaime Huertas, H Thomas Lee.

Cathepsins are one of the most abundant proteases within the lysosomes with diverse physiological effects ranging from immune responses, cell death and intracellular protein degradation. Cathepsins are involved in extracellular and systemic functions such as systemic inflammation and extracellular matrix degradation. Ischemia reperfusion (IR) injury is responsible for numerous diseases including myocardial infarction, acute kidney injury, stroke and acute graft failure after transplant surgery. Inflammation plays a major role in the reperfusion phase of IR injury and previous research has shown that cathepsins are key mediators of the inflammation cascade as well as apoptosis. Taken together, cathepsins modulation could provide potential therapeutic approaches to attenuate IR injury. The present review summarized the current understanding of various cathepsin subtypes, their major physiologic functions, their roles in multi‑organ IR injury and detailed selective cathepsin inhibitors with therapeutic potential.

Keywords: apoptosis; cell death; inflammation; lysosome; necrosis

DOI: https://doi.org/10.3892/mmr.2022.12885

Nat Rev Mol Cell Biol. 2022 Oct 27.

The mechanisms and roles of selective autophagy in mammals.

Jose Norberto S Vargas, Maho Hamasaki, Tsuyoshi Kawabata, Richard J Youle, Tamotsu Yoshimori.

Autophagy is a process that targets various intracellular elements for degradation. Autophagy can be non-selective - associated with the indiscriminate engulfment of cytosolic components - occurring in response to nutrient starvation and is commonly referred to as bulk autophagy. By contrast, selective autophagy degrades specific targets, such as damaged organelles (mitophagy, lysophagy, ER-phagy, ribophagy), aggregated proteins (aggrephagy) or invading bacteria (xenophagy), thereby being importantly involved in cellular quality control. Hence, not surprisingly, aberrant selective autophagy has been associated with various human pathologies, prominently including neurodegeneration and infection. In recent years, considerable progress has been made in understanding mechanisms governing selective cargo engulfment in mammals, including the identification of ubiquitin-dependent selective autophagy receptors such as p62, NBR1, OPTN and NDP52, which can bind cargo and ubiquitin simultaneously to initiate pathways leading to autophagy initiation and membrane recruitment. This progress opens the prospects for enhancing selective autophagy pathways to boost cellular quality control capabilities and alleviate pathology.

DOI: https://doi.org/10.1038/s41580-022-00542-2

Sci Adv. 2022 Oct 28. 8(43): eabn1702

Beyond autophagy: LC3-associated phagocytosis and endocytosis.

Carolina Peña-Martinez, Alexis D Rickman, Bradlee L Heckmann.

Noncanonical functions of the autophagy machinery in pathways including LC3-associated phagocytosis and LC3-associated endocytosis have garnered increasing interest in both normal physiology and pathobiology. New discoveries over the past decade of noncanonical uses of the autophagy machinery in these distinct molecular mechanisms have led to robust investigation into the roles of single-membrane LC3 lipidation. Noncanonical autophagy pathways have now been implicated in the regulation of multiple processes ranging from debris clearance, cellular signaling, and immune regulation and inflammation. Accumulating evidence is demonstrating roles in a variety of disease states including host-pathogen responses, autoimmunity, cancer, and neurological and neurodegenerative pathologies. Here, we broadly summarize the differences in the mechanistic regulation between autophagy and LAP and LANDO and highlight some of the key roles of LAP and LANDO in innate immune function, inflammation, and disease pathology.

DOI: https://doi.org/10.1126/sciadv.abn1702