bims-lymeca 2022-10-30 papers

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

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

J Cell Biol. 2022 Dec 05. pii: e202208103. [Epub ahead of print]221(12):

mTORC1 beyond anabolic metabolism: Regulation of cell death.

Jiajun Zhu, Hua Wang, Xuejun Jiang.

The mechanistic target of rapamycin complex 1 (mTORC1), a multi-subunit protein kinase complex, interrogates growth factor signaling with cellular nutrient and energy status to control metabolic homeostasis. Activation of mTORC1 promotes biosynthesis of macromolecules, including proteins, lipids, and nucleic acids, and simultaneously suppresses catabolic processes such as lysosomal degradation of self-constituents and extracellular components. Metabolic regulation has emerged as a critical determinant of various cellular death programs, including apoptosis, pyroptosis, and ferroptosis. In this article, we review the expanding knowledge on how mTORC1 coordinates metabolic pathways to impinge on cell death regulation. We focus on the current understanding on how nutrient status and cellular signaling pathways connect mTORC1 activity with ferroptosis, an iron-dependent cell death program that has been implicated in a plethora of human diseases. In-depth understanding of the principles governing the interaction between mTORC1 and cell death pathways can ultimately guide the development of novel therapies for the treatment of relevant pathological conditions.

DOI: https://doi.org/10.1083/jcb.202208103

Cell Chem Biol. 2022 Oct 24. pii: S2451-9456(22)00360-9. [Epub ahead of print]

Ferroptosis inhibition by lysosome-dependent catabolism of extracellular protein.

David A Armenta, Nouf N Laqtom, Grace Alchemy, Wentao Dong, Danielle Morrow, Carson D Poltorack, David A Nathanson, Monther Abu-Remalieh, Scott J Dixon.

Cancer cells need a steady supply of nutrients to evade cell death and proliferate. Depriving cancer cells of the amino acid cystine can trigger the non-apoptotic cell death process of ferroptosis. Here, we report that cancer cells can evade cystine deprivation-induced ferroptosis by uptake and catabolism of the cysteine-rich extracellular protein albumin. This protective mechanism is enhanced by mTORC1 inhibition and involves albumin degradation in the lysosome, predominantly by cathepsin B (CTSB). CTSB-dependent albumin breakdown followed by export of cystine from the lysosome via the transporter cystinosin fuels the synthesis of glutathione, which suppresses lethal lipid peroxidation. When cancer cells are grown under non-adherent conditions as spheroids, mTORC1 pathway activity is reduced, and albumin supplementation alone affords considerable protection against ferroptosis. These results identify the catabolism of extracellular protein within the lysosome as a mechanism that can inhibit ferroptosis in cancer cells.

Keywords: ROS; albumin; cancer; cathepsin; cell death; cysteine; ferroptosis; glutathione; lysosome; mTOR

DOI: https://doi.org/10.1016/j.chembiol.2022.10.006

Autophagy. 2022 Oct 26.

Autophagic perturbation caused by reduced lysosomal activity positively regulates cell competition.

Eilma Akter, Shunsuke Kon.

Newly emerging transformed epithelial cells are recognized and apically removed by surrounding normal cells through a biological event termed "cell competition". However, little is known about the mechanisms underlying this process. In a recent study, we describe that RASG12V/RasV12-transformed cells surrounded by normal cells exhibit decreased lysosomal activity accompanied with accumulation of autophagosomes. Restoration of low lysosomal activity or inhibition of autophagosome formation significantly antagonizes apical extrusion of RASG12V cells, suggesting that non-degradable autophagosomes are required for cell competition. Notably, analysis of a cell competition mouse model demonstrates that macroautophagy/autophagy-ablated RASG12V cells are less readily eliminated by cell competition, and remaining transformed cells destroy ductal integrity, leading to chronic pancreatitis. Thus, our findings illuminate a critical role for non-degradable autophagosomes in cell competition and reveal a homeostasis-preserving role of autophagy upon emergence of transformed cells.

Keywords: cell competition; hindered autophagic flux; lysosomal dysfunction; non-degradable autophagosomes; pancreatic cancer

DOI: https://doi.org/10.1080/15548627.2022.2140559

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