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  1. Article ; Online: Emerging roles of the MiT/TFE factors in cancer.

    Zoncu, Roberto / Perera, Rushika M

    Trends in cancer

    2023  Volume 9, Issue 10, Page(s) 817–827

    Abstract: The microphthalmia/transcription factor E (MiT/TFE) transcription factors (TFs; TFEB, TFE3, MITF, and TFEC) play a central role in cellular catabolism and quality control and are subject to extensive layers of regulation that influence their localization, ...

    Abstract The microphthalmia/transcription factor E (MiT/TFE) transcription factors (TFs; TFEB, TFE3, MITF, and TFEC) play a central role in cellular catabolism and quality control and are subject to extensive layers of regulation that influence their localization, stability, and activity. Recent studies have highlighted a broader role for these TFs in driving diverse stress-adaptation pathways, which manifest in a context- and tissue-dependent manner. Several human cancers upregulate the MiT/TFE factors to survive extreme fluctuations in nutrients, energy, and pharmacological challenges. Emerging data suggest that reduced activity of the MiT/TFE factors can also promote tumorigenesis. Here, we outline recent findings relating to novel mechanisms of regulation and activity of MiT/TFE proteins across some of the most aggressive human cancers.
    MeSH term(s) Humans ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism ; Microphthalmia-Associated Transcription Factor/genetics ; Microphthalmia-Associated Transcription Factor/metabolism ; Microphthalmos/metabolism ; Lysosomes/metabolism ; Neoplasms/genetics ; Neoplasms/metabolism
    Chemical Substances Basic Helix-Loop-Helix Leucine Zipper Transcription Factors ; Microphthalmia-Associated Transcription Factor
    Language English
    Publishing date 2023-07-01
    Publishing country United States
    Document type Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2852626-0
    ISSN 2405-8025 ; 2405-8033 ; 2405-8033
    ISSN (online) 2405-8025 ; 2405-8033
    ISSN 2405-8033
    DOI 10.1016/j.trecan.2023.06.005
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  2. Article ; Online: PITTching in for lysosome repair.

    Goul, Claire S / Zoncu, Roberto

    Developmental cell

    2022  Volume 57, Issue 20, Page(s) 2347–2349

    Abstract: 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 ... ...

    Abstract 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.
    MeSH term(s) Triacetoneamine-N-Oxyl/metabolism ; Lysosomes/metabolism ; Phosphatidylinositols/metabolism
    Chemical Substances Triacetoneamine-N-Oxyl (2896-70-0) ; Phosphatidylinositols
    Language English
    Publishing date 2022-10-25
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2054967-2
    ISSN 1878-1551 ; 1534-5807
    ISSN (online) 1878-1551
    ISSN 1534-5807
    DOI 10.1016/j.devcel.2022.09.014
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  3. Article ; Online: Author Correction: The molecular basis of nutrient sensing and signalling by mTORC1 in metabolism regulation and disease.

    Goul, Claire / Peruzzo, Roberta / Zoncu, Roberto

    Nature reviews. Molecular cell biology

    2023  Volume 24, Issue 12, Page(s) 934

    Language English
    Publishing date 2023-09-01
    Publishing country England
    Document type Published Erratum
    ZDB-ID 2031313-5
    ISSN 1471-0080 ; 1471-0072
    ISSN (online) 1471-0080
    ISSN 1471-0072
    DOI 10.1038/s41580-023-00670-3
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  4. Article ; Online: Built to last: lysosome remodeling and repair in health and disease.

    Zoncu, Roberto / Perera, Rushika M

    Trends in cell biology

    2022  Volume 32, Issue 7, Page(s) 597–610

    Abstract: Lysosomes play major roles in growth regulation and catabolism and are recognized as critical mediators of cellular remodeling. An emerging theme is how the lysosome is itself subjected to extensive remodeling in order to perform specific tasks that meet ...

    Abstract Lysosomes play major roles in growth regulation and catabolism and are recognized as critical mediators of cellular remodeling. An emerging theme is how the lysosome is itself subjected to extensive remodeling in order to perform specific tasks that meet the changing demands of the cell. Accordingly, lysosomes can sustain physical damage and undergo dramatic changes in composition following pathogen infection, accumulation of protein aggregates, or cellular transformation, necessitating dedicated pathways for their repair, remodeling, and restoration. In this review, we focus on emerging molecular mechanisms for piecemeal remodeling of lysosomal components and wholesale repair and discuss their implications in physiological and pathogenic challenges such as cancer, neurodegeneration, and pathogen infection.
    MeSH term(s) Humans ; Lysosomes/metabolism ; Neoplasms/pathology
    Language English
    Publishing date 2022-02-02
    Publishing country England
    Document type Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 30122-x
    ISSN 1879-3088 ; 0962-8924
    ISSN (online) 1879-3088
    ISSN 0962-8924
    DOI 10.1016/j.tcb.2021.12.009
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  5. Article ; Online: Organelle transporters and inter-organelle communication as drivers of metabolic regulation and cellular homeostasis.

    Jain, Aakriti / Zoncu, Roberto

    Molecular metabolism

    2022  Volume 60, Page(s) 101481

    Abstract: Background: Spatial compartmentalization of metabolic pathways within membrane-separated organelles is key to the ability of eukaryotic cells to precisely regulate their biochemical functions. Membrane-bound organelles such as mitochondria, endoplasmic ... ...

    Abstract Background: Spatial compartmentalization of metabolic pathways within membrane-separated organelles is key to the ability of eukaryotic cells to precisely regulate their biochemical functions. Membrane-bound organelles such as mitochondria, endoplasmic reticulum (ER) and lysosomes enable the concentration of metabolic precursors within optimized chemical environments, greatly accelerating the efficiency of both anabolic and catabolic reactions, enabling division of labor and optimal utilization of resources. However, metabolic compartmentalization also poses a challenge to cells because it creates spatial discontinuities that must be bridged for reaction cascades to be connected and completed. To do so, cells employ different methods to coordinate metabolic fluxes occurring in different organelles, such as membrane-localized transporters to facilitate regulated metabolite exchange between mitochondria and lysosomes, non-vesicular transport pathways via physical contact sites connecting the ER with both mitochondria and lysosomes, as well as localized regulatory signaling processes that coordinately regulate the activity of all these organelles.
    Scope of review: This review covers how cells use membrane transporters, membrane contact sites, and localized signaling pathways to mediate inter-organelle communication and coordinate metabolism. We also describe how disruption of inter-organelle communication is an emerging driver in a multitude of diseases, from cancer to neurodegeneration.
    Major conclusions: Effective communication among organelles is essential to cellular health and function. Identifying the major molecular players involved in mediating metabolic coordination between organelles will further our understanding of cellular metabolism in health and lead us to design better therapeutics against dysregulated metabolism in disease.
    MeSH term(s) Communication ; Endoplasmic Reticulum/metabolism ; Homeostasis ; Membrane Transport Proteins/metabolism ; Mitochondrial Membranes/metabolism
    Chemical Substances Membrane Transport Proteins
    Language English
    Publishing date 2022-03-25
    Publishing country Germany
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 2708735-9
    ISSN 2212-8778 ; 2212-8778
    ISSN (online) 2212-8778
    ISSN 2212-8778
    DOI 10.1016/j.molmet.2022.101481
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  6. Article ; Online: The molecular basis of nutrient sensing and signalling by mTORC1 in metabolism regulation and disease.

    Goul, Claire / Peruzzo, Roberta / Zoncu, Roberto

    Nature reviews. Molecular cell biology

    2023  Volume 24, Issue 12, Page(s) 857–875

    Abstract: The Ser/Thr kinase mechanistic target of rapamycin (mTOR) is a central regulator of cellular metabolism. As part of mTOR complex 1 (mTORC1), mTOR integrates signals such as the levels of nutrients, growth factors, energy sources and oxygen, and triggers ... ...

    Abstract The Ser/Thr kinase mechanistic target of rapamycin (mTOR) is a central regulator of cellular metabolism. As part of mTOR complex 1 (mTORC1), mTOR integrates signals such as the levels of nutrients, growth factors, energy sources and oxygen, and triggers responses that either boost anabolism or suppress catabolism. mTORC1 signalling has wide-ranging consequences for the growth and homeostasis of key tissues and organs, and its dysregulated activity promotes cancer, type 2 diabetes, neurodegeneration and other age-related disorders. How mTORC1 integrates numerous upstream cues and translates them into specific downstream responses is an outstanding question with major implications for our understanding of physiology and disease mechanisms. In this Review, we discuss recent structural and functional insights into the molecular architecture of mTORC1 and its lysosomal partners, which have greatly increased our mechanistic understanding of nutrient-dependent mTORC1 regulation. We also discuss the emerging involvement of aberrant nutrient-mTORC1 signalling in multiple diseases.
    MeSH term(s) Humans ; Mechanistic Target of Rapamycin Complex 1/metabolism ; Multiprotein Complexes/metabolism ; Diabetes Mellitus, Type 2 ; TOR Serine-Threonine Kinases/metabolism ; Nutrients
    Chemical Substances Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; Multiprotein Complexes ; TOR Serine-Threonine Kinases (EC 2.7.11.1)
    Language English
    Publishing date 2023-08-23
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 2031313-5
    ISSN 1471-0080 ; 1471-0072
    ISSN (online) 1471-0080
    ISSN 1471-0072
    DOI 10.1038/s41580-023-00641-8
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  7. Article ; Online: Picking the arginine lock on PQLC2 cycling.

    Jain, Aakriti / Zoncu, Roberto

    Proceedings of the National Academy of Sciences of the United States of America

    2021  Volume 118, Issue 35

    MeSH term(s) Amino Acid Transport Systems, Basic ; Arginine
    Chemical Substances Amino Acid Transport Systems, Basic ; Arginine (94ZLA3W45F)
    Language English
    Publishing date 2021-08-27
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Comment
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.2112682118
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  8. Article ; Online: Organelle transporters and inter-organelle communication as drivers of metabolic regulation and cellular homeostasis

    Aakriti Jain / Roberto Zoncu

    Molecular Metabolism, Vol 60, Iss , Pp 101481- (2022)

    2022  

    Abstract: Background: Spatial compartmentalization of metabolic pathways within membrane-separated organelles is key to the ability of eukaryotic cells to precisely regulate their biochemical functions. Membrane-bound organelles such as mitochondria, endoplasmic ... ...

    Abstract Background: Spatial compartmentalization of metabolic pathways within membrane-separated organelles is key to the ability of eukaryotic cells to precisely regulate their biochemical functions. Membrane-bound organelles such as mitochondria, endoplasmic reticulum (ER) and lysosomes enable the concentration of metabolic precursors within optimized chemical environments, greatly accelerating the efficiency of both anabolic and catabolic reactions, enabling division of labor and optimal utilization of resources. However, metabolic compartmentalization also poses a challenge to cells because it creates spatial discontinuities that must be bridged for reaction cascades to be connected and completed. To do so, cells employ different methods to coordinate metabolic fluxes occurring in different organelles, such as membrane-localized transporters to facilitate regulated metabolite exchange between mitochondria and lysosomes, non-vesicular transport pathways via physical contact sites connecting the ER with both mitochondria and lysosomes, as well as localized regulatory signaling processes that coordinately regulate the activity of all these organelles. Scope of review: This review covers how cells use membrane transporters, membrane contact sites, and localized signaling pathways to mediate inter-organelle communication and coordinate metabolism. We also describe how disruption of inter-organelle communication is an emerging driver in a multitude of diseases, from cancer to neurodegeneration. Major conclusions: Effective communication among organelles is essential to cellular health and function. Identifying the major molecular players involved in mediating metabolic coordination between organelles will further our understanding of cellular metabolism in health and lead us to design better therapeutics against dysregulated metabolism in disease.
    Keywords Mitochondria ; Metabolism ; Contact sites ; mTORC1 ; Transporters ; Lysosome ; Internal medicine ; RC31-1245
    Subject code 570
    Language English
    Publishing date 2022-06-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: A zinc-sensing protein gives flies a gut feeling for growth.

    Citron, Y Rose / Zoncu, Roberto

    Nature

    2020  Volume 580, Issue 7802, Page(s) 187–188

    MeSH term(s) Animals ; Diptera ; Eating ; Humans ; Intestines/physiology ; Zinc
    Chemical Substances Zinc (J41CSQ7QDS)
    Language English
    Publishing date 2020-03-16
    Publishing country England
    Document type News ; Comment
    ZDB-ID 120714-3
    ISSN 1476-4687 ; 0028-0836
    ISSN (online) 1476-4687
    ISSN 0028-0836
    DOI 10.1038/d41586-020-00728-8
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  10. Article ; Online: The Lysosome at the Intersection of Cellular Growth and Destruction.

    Shin, Hijai R / Zoncu, Roberto

    Developmental cell

    2020  Volume 54, Issue 2, Page(s) 226–238

    Abstract: The lysosome is an essential catabolic organelle that consumes cellular biomass to regenerate basic building blocks that can fuel anabolic reactions. This simple view has evolved more recently to integrate novel functions of the lysosome as a key ... ...

    Abstract The lysosome is an essential catabolic organelle that consumes cellular biomass to regenerate basic building blocks that can fuel anabolic reactions. This simple view has evolved more recently to integrate novel functions of the lysosome as a key signaling center, which can steer the metabolic trajectory of cells in response to changes in nutrients, growth factors, and stress. Master protein kinases and transcription factors mediate the growth-promoting and catabolic activities of the lysosome and undergo a complex interplay that enables cellular adaptation to ever-changing metabolic conditions. Understanding how this coordination occurs will shed light on the fundamental logic of how the lysosome functions to control growth in the context of development, tissue homeostasis, and cancer.
    MeSH term(s) Animals ; Autophagy/physiology ; Cell Cycle/physiology ; Cell Proliferation/physiology ; Homeostasis/physiology ; Humans ; Mechanistic Target of Rapamycin Complex 1/metabolism ; Signal Transduction/physiology
    Chemical Substances Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1)
    Language English
    Publishing date 2020-06-30
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2054967-2
    ISSN 1878-1551 ; 1534-5807
    ISSN (online) 1878-1551
    ISSN 1534-5807
    DOI 10.1016/j.devcel.2020.06.010
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