bims-lymeca 2023-09-03 papers

Exp Mol Med. 2023 Sep 01.

Pancreatic β-cell mitophagy as an adaptive response to metabolic stress and the underlying mechanism that involves lysosomal Ca2+ release.

Soo-Jin Oh, Kihyoun Park, Seong Keun Sonn, Goo Taeg Oh, Myung-Shik Lee.

Mitophagy is an excellent example of selective autophagy that eliminates damaged or dysfunctional mitochondria, and it is crucial for the maintenance of mitochondrial integrity and function. The critical roles of autophagy in pancreatic β-cell structure and function have been clearly shown. Furthermore, morphological abnormalities and decreased function of mitochondria have been observed in autophagy-deficient β-cells, suggesting the importance of β-cell mitophagy. However, the role of authentic mitophagy in β-cell function has not been clearly demonstrated, as mice with pancreatic β-cell-specific disruption of Parkin, one of the most important players in mitophagy, did not exhibit apparent abnormalities in β-cell function or glucose homeostasis. Instead, the role of mitophagy in pancreatic β-cells has been investigated using β-cell-specific Tfeb-knockout mice (TfebΔβ-cell mice); Tfeb is a master regulator of lysosomal biogenesis or autophagy gene expression and participates in mitophagy. TfebΔβ-cell mice were unable to adaptively increase mitophagy or mitochondrial complex activity in response to high-fat diet (HFD)-induced metabolic stress. Consequently, TfebΔβ-cell mice exhibited impaired β-cell responses and further exacerbated metabolic deterioration after HFD feeding. TFEB was activated by mitochondrial or metabolic stress-induced lysosomal Ca2+ release, which led to calcineurin activation and mitophagy. After lysosomal Ca2+ release, depleted lysosomal Ca2+ stores were replenished by ER Ca2+ through ER→lysosomal Ca2+ refilling, which supplemented the low lysosomal Ca2+ capacity. The importance of mitophagy in β-cell function was also demonstrated in mice that developed β-cell dysfunction and glucose intolerance after treatment with a calcineurin inhibitor that hampered TFEB activation and mitophagy.

DOI: https://doi.org/10.1038/s12276-023-01055-4

Nat Metab. 2023 Aug 28.

Cell cycle-linked vacuolar pH dynamics regulate amino acid homeostasis and cell growth.

Voytek Okreglak, Rachel Ling, Maria Ingaramo, Nathaniel H Thayer, Alfred Millett-Sikking, Daniel E Gottschling.

Amino acid homeostasis is critical for many cellular processes. It is well established that amino acids are compartmentalized using pH gradients generated between organelles and the cytoplasm; however, the dynamics of this partitioning has not been explored. Here we develop a highly sensitive pH reporter and find that the major amino acid storage compartment in Saccharomyces cerevisiae, the lysosome-like vacuole, alkalinizes before cell division and re-acidifies as cells divide. The vacuolar pH dynamics require the uptake of extracellular amino acids and activity of TORC1, the v-ATPase and the cycling of the vacuolar specific lipid phosphatidylinositol 3,5-bisphosphate, which is regulated by the cyclin-dependent kinase Pho85 (CDK5 in mammals). Vacuolar pH regulation enables amino acid sequestration and mobilization from the organelle, which is important for mitochondrial function, ribosome homeostasis and cell size control. Collectively, our data provide a new paradigm for the use of dynamic pH-dependent amino acid compartmentalization during cell growth/division.

DOI: https://doi.org/10.1038/s42255-023-00872-1

Mol Cell. 2023 Aug 24. pii: S1097-2765(23)00640-8. [Epub ahead of print]

Lysosomal cystine governs ferroptosis sensitivity in cancer via cysteine stress response.

Robert V Swanda, Quanquan Ji, Xincheng Wu, Jingyue Yan, Leiming Dong, Yuanhui Mao, Saori Uematsu, Yizhou Dong, Shu-Bing Qian.

The amino acid cysteine and its oxidized dimeric form cystine are commonly believed to be synonymous in metabolic functions. Cyst(e)ine depletion not only induces amino acid response but also triggers ferroptosis, a non-apoptotic cell death. Here, we report that unlike general amino acid starvation, cyst(e)ine deprivation triggers ATF4 induction at the transcriptional level. Unexpectedly, it is the shortage of lysosomal cystine, but not the cytosolic cysteine, that elicits the adaptative ATF4 response. The lysosome-nucleus signaling pathway involves the aryl hydrocarbon receptor (AhR) that senses lysosomal cystine via the kynurenine pathway. A blockade of lysosomal cystine efflux attenuates ATF4 induction and sensitizes ferroptosis. To potentiate ferroptosis in cancer, we develop a synthetic mRNA reagent, CysRx, that converts cytosolic cysteine to lysosomal cystine. CysRx maximizes cancer cell ferroptosis and effectively suppresses tumor growth in vivo. Thus, intracellular nutrient reprogramming has the potential to induce selective ferroptosis in cancer without systematic starvation.

Keywords: AhR; cancer therapy; cysteine; cystine; ferroptosis; lysosome; mRNA; nutrient stress

DOI: https://doi.org/10.1016/j.molcel.2023.08.004

Cell Rep. 2023 Aug 30. pii: S2211-1247(23)01053-7. [Epub ahead of print]42(9): 113042

Ectopic expression of DOCK8 regulates lysosome-mediated pancreatic tumor cell invasion.

Omar L Gutierrez-Ruiz, Katherine M Johnson, Eugene W Krueger, Roseanne E Nooren, Nicole Cruz-Reyes, Carrie Jo Heppelmann, Tara L Hogenson, Martin E Fernandez-Zapico, Mark A McNiven, Gina L Razidlo.

Amplified lysosome activity is a hallmark of pancreatic ductal adenocarcinoma (PDAC) orchestrated by oncogenic KRAS that mediates tumor growth and metastasis, though the mechanisms underlying this phenomenon remain unclear. Using comparative proteomics, we found that oncogenic KRAS significantly enriches levels of the guanine nucleotide exchange factor (GEF) dedicator of cytokinesis 8 (DOCK8) on lysosomes. Surprisingly, DOCK8 is aberrantly expressed in a subset of PDAC, where it promotes cell invasion in vitro and in vivo. DOCK8 associates with lysosomes and regulates lysosomal morphology and motility, with loss of DOCK8 leading to increased lysosome size. DOCK8 promotes actin polymerization at the surface of lysosomes while also increasing the proteolytic activity of the lysosomal protease cathepsin B. Critically, depletion of DOCK8 significantly reduces cathepsin-dependent extracellular matrix degradation and impairs the invasive capacity of PDAC cells. These findings implicate ectopic expression of DOCK8 as a key driver of KRAS-driven lysosomal regulation and invasion in pancreatic cancer cells.

Keywords: CP: Cancer; DOCK8; Invasion; cathepsin B; lysosome; matrix degradation; metastasis; pancreatic cancer

DOI: https://doi.org/10.1016/j.celrep.2023.113042

Trends Endocrinol Metab. 2023 Aug 24. pii: S1043-2760(23)00152-2. [Epub ahead of print]

Lysosomal glucose sensing and glycophagy in metabolism.

Melina C Mancini, Robert C Noland, J Jason Collier, Susan J Burke, Krisztian Stadler, Timothy D Heden.

Lysosomes are cellular organelles that function to catabolize both extra- and intracellular cargo, act as a platform for nutrient sensing, and represent a core signaling node integrating bioenergetic cues to changes in cellular metabolism. Although lysosomal amino acid and lipid sensing in metabolism has been well characterized, lysosomal glucose sensing and the role of lysosomes in glucose metabolism is unrefined. This review will highlight the role of the lysosome in glucose metabolism with a focus on lysosomal glucose and glycogen sensing, glycophagy, and lysosomal glucose transport and how these processes impact autophagy and energy metabolism. Additionally, the role of lysosomal glucose metabolism in genetic and metabolic diseases will be briefly discussed.

Keywords: autophagy; carbohydrate sensing; glycogen; nutrient sensing

DOI: https://doi.org/10.1016/j.tem.2023.07.008

Onco Targets Ther. 2023 ;16 695-702

Spotlight on GOT2 in Cancer Metabolism.

Samuel A Kerk, Javier Garcia-Bermudez, Kivanc Birsoy, Mara H Sherman, Yatrik M Shah, Costas A Lyssiotis.

GOT2 is at the nexus of several critical metabolic pathways in homeostatic cellular and dysregulated cancer metabolism. Despite this, recent work has emphasized the remarkable plasticity of cancer cells to employ compensatory pathways when GOT2 is inhibited. Here, we review the metabolic roles of GOT2, highlighting findings in both normal and cancer cells. We emphasize how cancer cells repurpose cell intrinsic metabolism and their flexibility when GOT2 is inhibited. We close by using this framework to discuss key considerations for future investigations into cancer metabolism.

Keywords: mitochondria; nucleotides; pancreatic cancer; redox; transaminase; tumor microenvironment

DOI: https://doi.org/10.2147/OTT.S382161