bims-lypmec 2024-10-27 papers

J Biol Chem. 2024 Oct 19. pii: S0021-9258(24)02413-X. [Epub ahead of print] 107911

Lysosomal activity depends on TRPML1-mediated Ca2+ release coupled to incoming vesicle fusions.

Arindam Bhattacharjee, Hussein Abuammar, Gábor Juhász.

The lysosomal cation channel TRPML1/MCOLN1 facilitates autophagic degradation during amino acid starvation based on studies involving long-term TRMPL1 modulation. Here we show that lysosomal activation (more acidic pH and higher hydrolase activity) depends on incoming vesicle fusions. We identify an immediate, calcium-dependent role of TRPML1 in lysosomal activation through promoting autophagosome-lysosome fusions and lysosome acidification within 10-20 minutes of its pharmacological activation. Lysosomes also become more fusion competent upon TRPML1 activation via increased transport of lysosomal SNARE proteins syntaxin 7 and VAMP7 by SNARE carrier vesicles. We find that incoming vesicle fusion is a prerequisite for lysosomal Ca2+ efflux that leads to acidification and hydrolytic enzyme activation. Physiologically, the first vesicle fusions likely trigger generation of the phospholipid PI(3,5)P2 that activates TRPML1, and allosteric TRPML1 activation in the absence of PI(3,5)P2 restores autophagosome-lysosome fusion and rescues abnormal SNARE sequestration within lysosomes. We thus identify a prompt role of TRPML1-mediated calcium signaling in lysosomal fusions, activation, and SNARE trafficking.

Keywords: SNARE proteins; autophagy; ion channel; lysosomal acidification; membrane fusion

DOI: https://doi.org/10.1016/j.jbc.2024.107911

Traffic. 2024 Oct;25(10): e12957

Fluorescent Reporters, Imaging, and Artificial Intelligence Toolkits to Monitor and Quantify Autophagy, Heterophagy, and Lysosomal Trafficking Fluxes.

Mikhail Rudinskiy, Diego Morone, Maurizio Molinari.

Lysosomal compartments control the clearance of cell-own material (autophagy) or of material that cells endocytose from the external environment (heterophagy) to warrant supply of nutrients, to eliminate macromolecules or parts of organelles present in excess, aged, or containing toxic material. Inherited or sporadic mutations in lysosomal proteins and enzymes may hamper their folding in the endoplasmic reticulum (ER) and their lysosomal transport via the Golgi compartment, resulting in lysosomal dysfunction and storage disorders. Defective cargo delivery to lysosomal compartments is harmful to cells and organs since it causes accumulation of toxic compounds and defective organellar homeostasis. Assessment of resident proteins and cargo fluxes to the lysosomal compartments is crucial for the mechanistic dissection of intracellular transport and catabolic events. It might be combined with high-throughput screenings to identify cellular, chemical, or pharmacological modulators of these events that may find therapeutic use for autophagy-related and lysosomal storage disorders. Here, discuss qualitative, quantitative and chronologic monitoring of autophagic, heterophagic and lysosomal protein trafficking in fixed and live cells, which relies on fluorescent single and tandem reporters used in combination with biochemical, flow cytometry, light and electron microscopy approaches implemented by artificial intelligence-based technology.

Keywords: ER‐phagy; ER‐to‐lysosome‐associated degradation (ERLAD); artificial intelligence; autophagy; autophagy flux; endolysosomes (EL); heterophagy; lysosomal storage disorders (LSD); lysosomes; tandem fluorescent reporters

DOI: https://doi.org/10.1111/tra.12957

J Cell Sci. 2024 Oct 15. pii: jcs262020. [Epub ahead of print]137(20):

Imaging interorganelle contacts at a glance.

Maria Clara Zanellati, Chih-Hsuan Hsu, Sarah Cohen.

Eukaryotic cells are compartmentalized into membrane-bound organelles that must coordinate their responses to stimuli. One way that organelles communicate is via membrane contact sites (MCSs), sites of close apposition between organelles used for the exchange of ions, lipids and information. In this Cell Science at a Glance article and the accompanying poster, we describe an explosion of new methods that have led to exciting progress in this area and discuss key examples of how these methods have advanced our understanding of MCSs. We discuss how diffraction-limited and super-resolution fluorescence imaging approaches have provided important insight into the biology of interorganelle communication. We also describe how the development of multiple proximity-based methods has enabled the detection of MCSs with high accuracy and precision. Finally, we assess how recent advances in electron microscopy (EM), considered the gold standard for detecting MCSs, have allowed the visualization of MCSs and associated proteins in 3D at ever greater resolution.

Keywords: Biosensors; Electron microscopy; Light microscopy; Membrane contact sites; Organelles; Super-resolution microscopy

DOI: https://doi.org/10.1242/jcs.262020

Am J Physiol Heart Circ Physiol. 2024 Oct 25.

Recent Advances Associated with Cardiometabolic Remodeling in Diabetes-induced Heart Failure.

Gaurav Sharma, Shyam S Chaurasia, Mark A Carlson, Paras K Mishra.

Diabetes mellitus (DM) is characterized by chronic hyperglycemia, and despite intensive glycemic control, the risk of heart failure in diabetic patients remains high. Diabetes-induced heart failure (DHF) presents a unique metabolic challenge, driven by significant alterations in cardiac substrate metabolism, including increased reliance on fatty acid oxidation, reduced glucose utilization, and impaired mitochondrial function. These metabolic alterations lead to oxidative stress, lipotoxicity, and energy deficits, contributing to the progression of heart failure. Emerging research has identified novel mechanisms involved in the metabolic remodeling of diabetic hearts, such as autophagy dysregulation, epigenetic modifications, polyamine regulation, and branched-chain amino acid (BCAA) metabolism. These processes exacerbate mitochondrial dysfunction and metabolic inflexibility, further impairing cardiac function. Therapeutic interventions targeting these pathways-such as enhancing glucose oxidation, modulating fatty acid metabolism, and optimizing ketone body utilization-show promise in restoring metabolic homeostasis and improving cardiac outcomes. This review explores the key molecular mechanisms driving metabolic remodeling in diabetic hearts and advanced methodology, highlighting the latest therapeutic strategies to mitigate the progression of DHF. Understanding these emerging pathways offers new opportunities to develop targeted therapies that address the root metabolic causes of heart failure in diabetes.

Keywords: Cardiac metabolism; Diabetes mellitus; Metabolic therapies; Mitochondrial dysfunction; Oxidative stress

DOI: https://doi.org/10.1152/ajpheart.00539.2024

NPJ Aging. 2024 Oct 21. 10(1): 46

Cell senescence in cardiometabolic diseases.

Mandy O J Grootaert.

Cellular senescence has been implicated in many age-related pathologies including atherosclerosis, heart failure, age-related cardiac remodeling, diabetic cardiomyopathy and the metabolic syndrome. Here, we will review the characteristics of senescent cells and their endogenous regulators, and summarize the metabolic stressors that induce cell senescence. We will discuss the evidence of cell senescence in the onset and progression of several cardiometabolic diseases and the therapeutic potential of anti-senescence therapies.

DOI: https://doi.org/10.1038/s41514-024-00170-4