bims-lymeca 2022-09-04 papers

bims-lymeca

Biomed News

on Lysosome metabolism in cancer

Issue of 2022–09–04
ten papers selected by
Harilaos Filippakis, University of New England

A lysosomal regulatory circuit essential for the development and function of microglia.
The endoplasmic reticulum contributes to lysosomal tubulation/sorting driven by LRRK2.
Pumping Iron: Ferritinophagy Promotes Survival and Therapy Resistance in Pancreatic Cancer.
TRPML3 enhances drug resistance in non-small cell lung cancer cells by promoting Ca2+-mediated lysosomal trafficking.
Dual contribution of the mTOR pathway and of the metabolism of amino acids in prostate cancer.
V-ATPase inhibitor targets Ras-mutant cancers.
Spatiotemporal analysis of axonal autophagosome-lysosome dynamics reveals limited fusion events and slow maturation.
Life in lockdown: Orchestrating endoplasmic reticulum and lysosome homeostasis for quiescent cells.
Mid51/Fis1 mitochondrial oligomerization complex drives lysosomal untethering and network dynamics.
Rab GTPases: The principal players in crafting the regulatory landscape of endosomal trafficking.

Sci Adv. 2022 Sep 02. 8(35): eabp8321

A lysosomal regulatory circuit essential for the development and function of microglia.

Harini Iyer, Kimberle Shen, Ana M Meireles, William S Talbot.

As the primary phagocytic cells of the central nervous system, microglia exquisitely regulate their lysosomal activity to facilitate brain development and homeostasis. However, mechanisms that coordinate lysosomal activity with microglia development, chemotaxis, and function remain unclear. Here, we show that embryonic macrophages require the lysosomal guanosine triphosphatase (GTPase) RagA and the GTPase-activating protein Folliculin to colonize the brain in zebrafish. We demonstrate that embryonic macrophages in rraga mutants show increased expression of lysosomal genes but display significant down-regulation of immune- and chemotaxis-related genes. Furthermore, we find that RagA and Folliculin repress the key lysosomal transcription factor Tfeb and its homologs Tfe3a and Tfe3b in the macrophage lineage. Using RNA sequencing, we establish that Tfeb and Tfe3 are required for activation of lysosomal target genes under conditions of stress but not for basal expression of lysosomal pathways. Collectively, our data define a lysosomal regulatory circuit essential for macrophage development and function in vivo.

DOI: https://doi.org/10.1126/sciadv.abp8321
Mol Biol Cell. 2022 Aug 31. mbcE22040139

The endoplasmic reticulum contributes to lysosomal tubulation/sorting driven by LRRK2.

Luis Bonet-Ponce, Mark R Cookson.

Lysosomes are dynamic organelles that can remodel their membrane as an adaptive response to various cell signaling events including membrane damage. Recently, we have discovered that damaged lysosomes form and sort tubules into moving vesicles. We named this process LYTL for LYsosomal Tubulation/ sorting driven by LRRK2, as the Parkinson's disease protein LRRK2 promotes tubulation by recruiting the motor adaptor protein JIP4 to lysosomes via phosphorylated RAB proteins. Here we use spinning-disk microscopy combined with super-resolution to further characterize LYTL after membrane damage with LLOMe. We identified the endoplasmic reticulum (ER) colocalizing with sites of fission of lysosome-derived tubules. In addition, modifying the morphology of the ER by reducing ER tubules leads to a decrease in LYTL sorting suggesting that contact with tubular ER is necessary for lysosomal membrane sorting. Given the central roles of LRRK2 and lysosomal biology in PD, these discoveries are likely relevant to disease pathology and highlight interactions between organelles in this model. [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text].

DOI: https://doi.org/10.1091/mbc.E22-04-0139
Cancer Discov. 2022 Sep 02. 12(9): 2023-2025

Pumping Iron: Ferritinophagy Promotes Survival and Therapy Resistance in Pancreatic Cancer.

Vaibhav Jain, Ravi K Amaravadi.

SUMMARY: Autophagy is an adaptive response to metabolic and therapeutic stress, especially in treatment-refractory cancers such as pancreatic cancer. In this issue of Cancer Discovery, two groups establish ferritinophagy, a selective autophagy program that could become a drug target, as the mechanism that pumps iron into mitochondria via the lysosome, enabling survival and therapy resistance in pancreas cancer. See related article by Santana-Codina et al., p. 2180 (3). See related article by Ravichandran et al., p. 2198 (4).

DOI: https://doi.org/10.1158/2159-8290.CD-22-0734
Biochem Biophys Res Commun. 2022 Aug 23. pii: S0006-291X(22)01181-0. [Epub ahead of print]627 152-159

TRPML3 enhances drug resistance in non-small cell lung cancer cells by promoting Ca2+-mediated lysosomal trafficking.

Mi Seong Kim, Sei Hoon Yang, Min Seuk Kim.

  Lysosomes are emerging as versatile signaling hubs that mediate numerous cellular processes, including the development of drug resistance in cancer cells. Transient receptor potential mucolipin 3 (TRPML3), an endolysosomal Ca2+-permeable channel, is implicated in regulating lysosomal trafficking during endocytosis and autophagy. However, the role of TRPML3 in cancer progression remains unclear. In this study, we focused on identifying key molecules that modulate exosomal release triggered by lysosomal exocytosis during the development of gefitinib resistance in non-small cell lung cancer (NSCLC). We found that the basal release of exosomes and lysosomal exocytosis is higher in the gefitinib-resistant NSCLC cell line HCC827/GR than in the gefitinib-sensitive NSCLC cell line HCC827. Notably, exosomal release and lysosomal exocytosis were associated with an increase in TRPML3 expression. Lysosomal Ca2+ release via TRPML3 was triggered by the gefitinib-mediated elevation of lysosomal pH. Furthermore, TRPML3 deficiency enhanced the gefitinib-mediated increase in sub-G0 cell population, reduction of cell proliferation, and poly (ADP-ribose) polymerase cleavage. These data demonstrated that TRPML3 is a promising modulator of drug resistance. By sensing the elevation of lysosomal pH, it mediates lysosomal Ca2+ release, lysosomal trafficking and exocytosis, and exosomal release. Taken together, our study is the first to report the autonomous defense mechanism developed in NSCLC cells against the small-molecule tyrosine kinase inhibitor gefitinib, leading to acquired drug resistance.

Keywords:  Drug resistance; Gefitinib; Lysosome; Non-small cell lung cancer; Transient receptor potential channel

DOI:  https://doi.org/10.1016/j.bbrc.2022.08.051
Cell Oncol (Dordr). 2022 Aug 29.

Dual contribution of the mTOR pathway and of the metabolism of amino acids in prostate cancer.

Alejandro Schcolnik-Cabrera, Daniel Juárez-López.

   BACKGROUND: Prostate cancer is the leading cause of cancer in men, and its incidence increases with age. Among other risk factors, pre-existing metabolic diseases have been recently linked with prostate cancer, and our current knowledge recognizes prostate cancer as a condition with important metabolic anomalies as well. In malignancies, metabolic disorders are commonly associated with aberrations in mTOR, which is the master regulator of protein synthesis and energetic homeostasis. Although there are reports demonstrating the high dependency of prostate cancer cells for lipid derivatives and even for carbohydrates, the understanding regarding amino acids, and the relationship with the mTOR pathway ultimately resulting in metabolic aberrations, is still scarce.
CONCLUSIONS AND PERSPECTIVES: In this review, we briefly provide evidence supporting prostate cancer as a metabolic disease, and discuss what is known about mTOR signaling and prostate cancer. Next, we emphasized on the amino acids glutamine, leucine, serine, glycine, sarcosine, proline and arginine, commonly related to prostate cancer, to explore the alterations in their regulatory pathways and to link them with the associated metabolic reprogramming events seen in prostate cancer. Finally, we display potential therapeutic strategies for targeting mTOR and the referred amino acids, as experimental approaches to selectively attack prostate cancer cells.

Keywords:  Amino acids; Cancer metabolism; Prostate cancer; mTOR

DOI:  https://doi.org/10.1007/s13402-022-00706-4
Nat Rev Drug Discov. 2022 Sep 02.

V-ATPase inhibitor targets Ras-mutant cancers.

Sarah Crunkhorn.

DOI: https://doi.org/10.1038/d41573-022-00151-w
Mol Biol Cell. 2022 Aug 31. mbcE22030111

Spatiotemporal analysis of axonal autophagosome-lysosome dynamics reveals limited fusion events and slow maturation.

Sydney E Cason, Saurabh S Mogre, Erika L F Holzbaur, Elena F Koslover.

Macroautophagy is a homeostatic process required to clear cellular waste. Neuronal autophagosomes form constitutively in the distal tip of the axon and are actively transported toward the soma, with cargo degradation initiated en route. Cargo turnover requires autophagosomes to fuse with lysosomes to acquire degradative enzymes; however, directly imaging these fusion events in the axon is impractical. Here we use a quantitative model, parameterized and validated using data from primary hippocampal neurons, to explore the autophagosome maturation process. We demonstrate that retrograde autophagosome motility is independent from fusion, and that most autophagosomes fuse with only a few lysosomes during axonal transport. Our results indicate breakdown of the inner autophagosomal membrane is much slower in neurons than in non-neuronal cell types, highlighting the importance of this late maturation step. Together, rigorous quantitative measurements and mathematical modeling elucidate the dynamics of autophagosome-lysosome interaction and autophagosomal maturation in the axon. [Media: see text].

DOI: https://doi.org/10.1091/mbc.E22-03-0111
Mol Cell. 2022 Aug 25. pii: S1097-2765(22)00758-4. [Epub ahead of print]

Life in lockdown: Orchestrating endoplasmic reticulum and lysosome homeostasis for quiescent cells.

Andrew Murley, Kevin Wickham, Andrew Dillin.

  Cellular quiescence-reversible exit from the cell cycle-is an important feature of many cell types important for organismal health. Quiescent cells activate protective mechanisms that allow their persistence in the absence of growth and division for long periods of time. Aging and cellular dysfunction compromise the survival and re-activation of quiescent cells over time. Counteracting this decline are two interconnected organelles that lie at opposite ends of the secretory pathway: the endoplasmic reticulum and lysosomes. In this review, we highlight recent studies exploring the roles of these two organelles in quiescent cells from diverse contexts and speculate on potential other roles they may play, such as through organelle contact sites. Finally, we discuss emerging models of cellular quiescence, utilizing new cell culture systems and model organisms, that are suited to the mechanistic investigation of the functions of these organelles in quiescent cells.

Keywords:  ER; aging; lysosome; quiescence; stem cells

DOI:  https://doi.org/10.1016/j.molcel.2022.08.005
J Cell Biol. 2022 Oct 03. pii: e202206140. [Epub ahead of print]221(10):

Mid51/Fis1 mitochondrial oligomerization complex drives lysosomal untethering and network dynamics.

Yvette C Wong, Soojin Kim, Jasmine Cisneros, Catherine G Molakal, Pingping Song, Steven J Lubbe, Dimitri Krainc.

Lysosomes are highly dynamic organelles implicated in multiple diseases. Using live super-resolution microscopy, we found that lysosomal tethering events rarely undergo lysosomal fusion, but rather untether over time to reorganize the lysosomal network. Inter-lysosomal untethering events are driven by a mitochondrial Mid51/Fis1 complex that undergoes coupled oligomerization on the outer mitochondrial membrane. Importantly, Fis1 oligomerization mediates TBC1D15 (Rab7-GAP) mitochondrial recruitment to drive inter-lysosomal untethering via Rab7 GTP hydrolysis. Moreover, inhibiting Fis1 oligomerization by either mutant Fis1 or a Mid51 oligomerization mutant potentially associated with Parkinson's disease prevents lysosomal untethering events, resulting in misregulated lysosomal network dynamics. In contrast, dominant optic atrophy-linked mutant Mid51, which does not inhibit Mid51/Fis1 coupled oligomerization, does not disrupt downstream lysosomal dynamics. As Fis1 conversely also regulates Mid51 oligomerization, our work further highlights an oligomeric Mid51/Fis1 mitochondrial complex that mechanistically couples together both Drp1 and Rab7 GTP hydrolysis machinery at mitochondria-lysosome contact sites. These findings have significant implications for organelle networks in cellular homeostasis and human disease.

DOI: https://doi.org/10.1083/jcb.202206140
Comput Struct Biotechnol J. 2022 ;20 4464-4472

Rab GTPases: The principal players in crafting the regulatory landscape of endosomal trafficking.

Jing Zhang, Zongyan Jiang, Anbing Shi.

After endocytosis, diverse cargos are sorted into endosomes and directed to various destinations, including extracellular macromolecules, membrane lipids, and membrane proteins. Some cargos are returned to the plasma membrane via endocytic recycling. In contrast, others are delivered to the Golgi apparatus through the retrograde pathway, while the rest are transported to late endosomes and eventually to lysosomes for degradation. Rab GTPases are major regulators that ensure cargos are delivered to their proper destinations. Rabs are localized to distinct endosomes and play predominant roles in membrane budding, vesicle formation and motility, vesicle tethering, and vesicle fusion by recruiting effectors. The cascades between Rabs via shared effectors or the recruitment of Rab activators provide an additional layer of spatiotemporal regulation of endocytic trafficking. Notably, several recent studies have indicated that disorders of Rab-mediated endocytic transports are closely associated with diseases such as immunodeficiency, cancer, and neurological disorders.

DOI: https://doi.org/10.1016/j.csbj.2022.08.016