bims-lypmec 2023-12-24 papers

Curr Biol. 2023 Dec 18. pii: S0960-9822(23)01489-6. [Epub ahead of print]33(24): R1289-R1291

Nutrient signaling: Starvation flips a phosphoinositide switch on lysosomal catabolism.

Lysosomes are highly dynamic organelles that rapidly respond to changes in cellular nutrient status. A new study identifies a phosphoinositide switch that dictates lysosome function during nutrient starvation.

DOI: https://doi.org/10.1016/j.cub.2023.10.066

Trends Cell Biol. 2023 Dec 15. pii: S0962-8924(23)00238-6. [Epub ahead of print]

Lysosomal microautophagy: an emerging dimension in mammalian autophagy.

Yoshihiko Kuchitsu, Tomohiko Taguchi.

Autophagy is a self-catabolic process through which cellular components are delivered to lysosomes for degradation. There are three types of autophagy, i.e., macroautophagy, chaperone-mediated autophagy (CMA), and microautophagy. In macroautophagy, a portion of the cytoplasm is wrapped by the autophagosome, which then fuses with lysosomes and delivers the engulfed cytoplasm for degradation. In CMA, the translocation of cytosolic substrates to the lysosomal lumen is directly across the limiting membrane of lysosomes. In microautophagy, lytic organelles, including endosomes or lysosomes, take up a portion of the cytoplasm directly. Although macroautophagy has been investigated extensively, microautophagy has received much less attention. Nonetheless, it has become evident that microautophagy plays a variety of cellular roles from yeast to mammals. Here we review the very recent updates of microautophagy. In particular, we focus on the feature of the degradative substrates and the molecular machinery that mediates microautophagy.

Keywords: ESCRT complex; K63-linked ubiquitination; lysosome; microautophagy; vacuole

DOI: https://doi.org/10.1016/j.tcb.2023.11.005

Chem Sci. 2023 Dec 20. 15(1): 102-112

Unveiling autophagy and aging through time-resolved imaging of lysosomal polarity with a delayed fluorescent emitter.

Subhadeep Das, Abhilasha Batra, Subhankar Kundu, Rati Sharma, Abhijit Patra.

Detecting the lysosomal microenvironmental changes like viscosity, pH, and polarity during their dynamic interorganelle interactions remains an intriguing area that facilitates the elucidation of cellular homeostasis. The subtle variation of physiological conditions can be assessed by deciphering the lysosomal microenvironments during lysosome-organelle interactions, closely related to autophagic pathways leading to various cellular disorders. Herein, we shed light on the dynamic lysosomal polarity in live cells and a multicellular model organism, Caenorhabditis elegans (C. elegans), through time-resolved imaging employing a thermally activated delayed fluorescent probe, DC-Lyso. The highly photostable and cytocompatible DC-Lyso rapidly labels the lysosomes (within 1 min of incubation) and exhibits red luminescence and polarity-sensitive long lifetime under the cellular environment. The distinct variation in the fluorescence lifetime of DC-Lyso suggests an increase in local polarity during the lysosomal dynamics and interorganelle interactions, including lipophagy and mitophagy. The lifetime imaging analysis reveals increasing lysosomal polarity as an indicator for probing the successive development of C. elegans during aging. The in vivo microsecond timescale imaging of various cancerous cell lines and C. elegans, as presented here, therefore, expands the scope of delayed fluorescent emitters for unveiling complex biological processes.

DOI: https://doi.org/10.1039/d3sc02450d

Cancer Lett. 2023 Dec 20. pii: S0304-3835(23)00550-5. [Epub ahead of print] 216599

Emerging roles of lysosome homeostasis (repair, lysophagy and biogenesis) in cancer progression and therapy.

Nitish Chauhan, Birija Sankar Patro.

In the era of personalized therapy, precise targeting of subcellular organelles holds great promise for cancer modality. Taking into consideration that lysosome represents the intersection site in numerous endosomal trafficking pathways and their modulation in cancer growth, progression, and resistance against cancer therapies, the lysosome is proposed as an attractive therapeutic target for cancer treatment. Based on the recent advances, the current review provides a comprehensive understanding of molecular mechanisms of lysosome homeostasis under 3R responses: Repair, Removal (lysophagy) and Regeneration of lysosomes. These arms of 3R responses have distinct role in lysosome homeostasis although their interdependency along with switching between the pathways still remain elusive. Recent advances underpinning the crucial role of (1) ESCRT complex dependent/independent repair of lysosome, (2) various Galectins-based sensing and ubiquitination in lysophagy and (3) TFEB/TFE proteins in lysosome regeneration/biogenesis of lysosome are outlined. Later, we also explore how these recent advancements may aid in development of phytochemicals and pharmacological agents for targeting lysosomes for efficient cancer therapy. Some of these lysosome targeting agents, which are now at various stages of clinical trials and patents, are also emphasised in this review.

Keywords: Lysophagy; Lysosome biogenesis: oxidative stress; Lysosome membrane permeabilization; Lysosome repair

DOI: https://doi.org/10.1016/j.canlet.2023.216599

Cancer Commun (Lond). 2023 Dec 22.

Glucose-mediated mitochondrial reprogramming by cholesterol export at TM4SF5-enriched mitochondria-lysosome contact sites.

Ji Eon Kim, So-Young Park, Chulhwan Kwak, Yoonji Lee, Dae-Geun Song, Jae Woo Jung, Haesong Lee, Eun-Ae Shin, Yangie Pinanga, Kyung-Hee Pyo, Eun Hae Lee, Wonsik Kim, Soyeon Kim, Chang-Duck Jun, Jeanho Yun, Sun Choi, Hyun-Woo Rhee, Kwang-Hyeon Liu, Jung Weon Lee.

BACKGROUND: Transmembrane 4 L six family member 5 (TM4SF5) translocates subcellularly and functions metabolically, although it is unclear how intracellular TM4SF5 translocation is linked to metabolic contexts. It is thus of interests to understand how the traffic dynamics of TM4SF5 to subcellular endosomal membranes are correlated to regulatory roles of metabolisms.
METHODS: Here, we explored the metabolic significance of TM4SF5 localization at mitochondria-lysosome contact sites (MLCSs), using in vitro cells and in vivo animal systems, via approaches by immunofluorescence, proximity labelling based proteomics analysis, organelle reconstitution etc. RESULTS: Upon extracellular glucose repletion following depletion, TM4SF5 became enriched at MLCSs via an interaction between mitochondrial FK506-binding protein 8 (FKBP8) and lysosomal TM4SF5. Proximity labeling showed molecular clustering of phospho-dynamic-related protein I (DRP1) and certain mitophagy receptors at TM4SF5-enriched MLCSs, leading to mitochondrial fission and autophagy. TM4SF5 bound NPC intracellular cholesterol transporter 1 (NPC1) and free cholesterol, and mediated export of lysosomal cholesterol to mitochondria, leading to impaired oxidative phosphorylation but intact tricarboxylic acid (TCA) cycle and β-oxidation. In mouse models, hepatocyte Tm4sf5 promoted mitophagy and cholesterol transport to mitochondria, both with positive relations to liver malignancy.
CONCLUSIONS: Our findings suggested that TM4SF5-enriched MLCSs regulate glucose catabolism by facilitating cholesterol export for mitochondrial reprogramming, presumably while hepatocellular carcinogenesis, recapitulating aspects for hepatocellular carcinoma metabolism with mitochondrial reprogramming to support biomolecule synthesis in addition to glycolytic energetics.

Keywords: cholesterol; fluorescent imaging; glucose catabolism; hepatocellular carcinogenesis; membrane contact sites; mitochondria function; mitophagy; oxidative phosphorylation; protein-protein interaction; tetraspanin

DOI: https://doi.org/10.1002/cac2.12510

Diab Vasc Dis Res. 2023 Nov-Dec;20(6):20(6): 14791641231205428

Molecular mechanisms of diabetic heart disease: Insights from transcriptomic technologies.

Marcella Conning-Rowland, Richard M Cubbon.

Over half a billion adults across the world have diabetes mellitus (DM). This has a wide-ranging impact on their health, including more than doubling their risk of major cardiovascular events, in comparison to age-sex matched individuals without DM. Notably, the risk of heart failure is particularly increased, even when coronary artery disease and hypertension are not present. Macro- and micro-vascular complications related to endothelial cell (EC) dysfunction are a systemic feature of DM and can affect the heart. However, it remains unclear to what extent these and other factors underpin myocardial dysfunction and heart failure linked with DM. Use of unbiased 'omics approaches to profile the molecular environment of the heart offers an opportunity to identify novel drivers of cardiac dysfunction in DM. Multiple transcriptomics studies have characterised the whole myocardium or isolated cardiac ECs. We present a systematic summary of relevant studies, which identifies common themes including alterations in both myocardial fatty acid metabolism and inflammation. These findings prompt further research focussed on these processes to validate potentially causal factors for prioritisation into therapeutic development pipelines.

Keywords: Diabetes; RNA-sequencing; diabetic cardiomyopathy; gene expression; heart; transcriptomics

DOI: https://doi.org/10.1177/14791641231205428