bims-lymeca 2023-01-22 papers

Biol Chem. 2023 Jan 20.

The role of lysosomes in lipid homeostasis.

Florian Fröhlich, Ayelén González Montoro.

Lipids function as the major building blocks of cellular membranes, as signaling molecules and as energy stores for metabolism. These important functions require a precise regulation of lipid biosynthesis, transport, turnover and storage. Lipids are exchanged among organelles through a sophisticated network of vesicular and non-vesicular transport routes. Lysosomes, as the main catabolic organelle, are at the center of this network and have recently evolved as one of the master-regulators of cellular lipid metabolism. Lipids from both endogenous and exogenous sources can be processed, sensed and sorted in and out of the lysosome. In this review, we focus on the role of the lysosome in lipid catabolism, transport and signaling. We highlight recent discoveries on the transport of lipids out of the lysosomal lumen and their exchange with other organelles via membrane contact sites. We also discuss the direct role of lysosomal lipids in the TORC1 signaling pathway, a regulator of cellular metabolism. Finally, we address lysosomal biogenesis, its role in the sorting of lipid metabolic enzymes and the dysregulation of these processes in disease.

Keywords: TORC1; contact sites; lipids; lysosome; sphingolipids; vacuole

DOI: https://doi.org/10.1515/hsz-2022-0287

JCI Insight. 2023 Jan 17. pii: e162498. [Epub ahead of print]

TFEB-mediated lysosomal exocytosis alleviates high fat diet-induced lipotoxicity in the kidney.

Obesity is a major risk factor for end-stage kidney disease. We previously found that lysosomal dysfunction and impaired autophagic flux contributed to lipotoxicity in obesity-related kidney disease, both in humans and experimental animal models. However, the regulatory factors involved in countering renal lipotoxicity are largely unknown. Here we found that palmitic acid (PA) strongly promoted dephosphorylation and nuclear translocation of transcription factor EB (TFEB) by inhibiting the mechanistic target of rapamycin kinase complex 1 (MTORC1) pathway in a Rag GTPase-dependent manner, although these effects gradually diminished after extended treatment. We then investigated the role of TFEB in the pathogenesis of obesity-related kidney disease. Proximal tubular epithelial cell (PTEC)-specific Tfeb-deficient mice fed a high-fat diet (HFD) exhibited greater phospholipid accumulation in enlarged lysosomes, which manifested as multilamellar bodies (MLBs). Activated TFEB mediated lysosomal exocytosis of phospholipids, which help reduce MLB accumulation in PTECs. Furthermore, HFD-fed PTEC-specific Tfeb-deficient mice showed autophagic stagnation and exacerbated injury upon renal ischemia-reperfusion. Finally, higher body mass index was associated with increased vacuolation and decreased nuclear TFEB in the proximal tubules of chronic kidney disease patients. These results indicate a critical role of TFEB-mediated lysosomal exocytosis in counteracting renal lipotoxicity.

Keywords: Chronic kidney disease; Lysosomes; Metabolism; Nephrology; Obesity

DOI: https://doi.org/10.1172/jci.insight.162498

Biomater Sci. 2023 Jan 19.

Dual stimuli-responsive cross-linked nanoassemblies from an amphiphilic mannose-6-phosphate based tri-block copolymer for lysosomal membrane permeabilization.

Basudeb Mondal, Abinash Padhy, Saptarshi Maji, Arnab Gupta, Sayam Sen Gupta.

Stimuli-responsive cross-linked nanocarriers that can induce lysosomal cell death (LCD) via lysosomal membrane permeabilization (LMP) represent a new class of delivery platforms and have attracted the attention of researchers in the biomedical field. The advantages of such cross-linked nanocarriers are as follows (i) they remain intact during blood circulation; and (ii) they reach the target site via specific receptor-mediated endocytosis leading to the enhancement of therapeutic efficacy and reduction of side effects. Herein, we have synthesized a mannose-6-phosphate (M6P) based amphiphilic ABC type tri-block copolymer having two chains of FDA-approved poly(ε-caprolactone) (PCL) as the hydrophobic block, and poly(S-(o-nitrobenzyl)-L-cysteine) (NBC) acts as the photoresponsive crosslinker block. Two different tri-block copolymers, [(PCL35)2-b-NBC20-b-M6PGP20] and [(PCL35)2-b-NBC15-b-M6PGP20], were synthesized which upon successful self-assembly initially formed spherical uncross-linked "micellar-type" aggregates (UCL-M) and vesicles (UCL-V), respectively. The uncross-linked nanocarriers upon UV treatment for thirty minutes were covalently crosslinked in the middle PNBC block giving rise to the di-sulfide bonds and forming interface cross-linked "micellar-type" aggregates (ICL-M) and vesicles (ICL-V). DLS, TEM, and AFM techniques were used to successfully characterize the morphology of these nanocarriers. The dual stimuli (redox and enzyme) responsiveness of the cross-linked nanocarriers and their trafficking to the lysosome in mammalian cells via receptor-mediated endocytosis was probed using confocal microscopy images. Furthermore, the addition of a chloroquine (CQ, a known lysosomotropic agent) encapsulated cross-linked nanocarrier (CQ@ICL-V) to non-cancerous (HEK-293T) cells and liver (HepG2), and breast cancer cells (MDA-MB-231) was found to initiate lysosomal membrane permeabilization (LMP) followed by lysosomal destabilization which eventually led to lysosomal cell death (LCD). Due to the targeted delivery of CQ to the lysosomes of cancerous cells, almost a 90% smaller amount of CQ was able to achieve similar cell death to CQ alone.

DOI: https://doi.org/10.1039/d2bm02110b

Biomedicines. 2023 Jan 14. pii: 213. [Epub ahead of print]11(1):

The Biology of Lysosomes: From Order to Disorder.

Olga Amaral, Mariana Martins, Ana Rita Oliveira, Ana Joana Duarte, Inês Mondragão-Rodrigues, M Fátima Macedo.

Since its discovery in 1955, the understanding of the lysosome has continuously increased. Once considered a mere waste removal system, the lysosome is now recognised as a highly crucial cellular component for signalling and energy metabolism. This notable evolution raises the need for a summarized review of the lysosome's biology. As such, throughout this article, we will be compiling the current knowledge regarding the lysosome's biogenesis and functions. The comprehension of this organelle's inner mechanisms is crucial to perceive how its impairment can give rise to lysosomal disease (LD). In this review, we highlight some examples of LD fine-tuned mechanisms that are already established, as well as others, which are still under investigation. Even though the understanding of the lysosome and its pathologies has expanded through the years, some of its intrinsic molecular aspects remain unknown. In order to illustrate the complexity of the lysosomal diseases we provide a few examples that have challenged the established single gene-single genetic disorder model. As such, we believe there is a strong need for further investigation of the exact abnormalities in the pathological pathways in lysosomal disease.

Keywords: endocytic pathway; lysosomal disease; lysosome; lysosome biogenesis and function

DOI: https://doi.org/10.3390/biomedicines11010213

Mol Oncol. 2023 Jan 17.

Rational combination of SHP2 and mTOR inhibition for the treatment of hepatocellular carcinoma.

Antonio Mulero-Sánchez, Christel Fa Ramirez, Aimée du Chatinier, Hui Wang, Sofie J I Koomen, Ji-Ying Song, Marnix Hp de Groot, Cor Lieftink, Astrid Bosma, Artur Burylo, Olaf van Tellingen, Roderick L Beijersbergen, Cun Wang, Leila Akkari, René Bernards, Sara Mainardi.

Liver cancer is the 4th cause of cancer-related death worldwide, with hepatocellular carcinoma (HCC) being the main primary malignancy affecting the liver. Unfortunately, there are still limited therapeutic options for HCC, and even the latest advances have only increased the overall survival modestly. Thus, new treatment strategies and rational drug combinations are urgently needed. Reactivation of receptor tyrosine kinases (RTKs) has been described as a mechanism of intrinsic resistance to targeted therapies in a variety of cancers, including inhibitors of mTOR. The design of rational combination therapies to overcome this type of resistance is complicated by the notion that multiple RTKs can be upregulated during the acquisition of resistance. SHP2, encoded by the gene PTPN11, acts downstream of virtually all RTKs, and has proven to be a good target for small molecule inhibitors. Here, we report activation of multiple RTKs upon mTOR inhibition in HCC which, through SHP2, leads to reactivation of the mTOR pathway. We show that co-inhibition of both mTOR and SHP2 is highly synergistic in vitro by triggering apoptosis. More importantly, the combination is well-tolerated and outperforms the monotherapies in impairing tumor growth in multiple HCC mouse models. Our findings suggest a novel rational combination therapy for the treatment of HCC.

Keywords: Hepatocellular carcinoma; Receptors tyrosine kinase; SHP2; combination; mTOR; therapy

DOI: https://doi.org/10.1002/1878-0261.13377