bims-lycede 2025-10-26 papers

Dev Cell. 2025 Oct 20. pii: S1534-5807(25)00570-2. [Epub ahead of print]60(20): 2701-2702

ATG9 assists lipid replenishment for lysosome membrane repair.

Lysosomal membranes can be permeabilized under various conditions with detrimental consequences for the cell. In this issue, de Tito et al. report that the lipid scramblase ATG9, best known for its role in autophagosome formation, helps distribute lipids from the ER to reseal the limiting membrane and restore lysosomal function.

DOI: https://doi.org/10.1016/j.devcel.2025.09.010

Trends Cell Biol. 2025 Oct 17. pii: S0962-8924(25)00222-3. [Epub ahead of print]

Roles of lysosomal small-molecule transporters in metabolism and signaling.

Markus Damme, Océane Guelle, Christian Löw, Bruno Gasnier.

Lysosomes degrade damaged or unwanted cell/tissue components and recycle their building blocks through small-molecule transporters of the lysosomal membrane. They also act as signaling hubs that sense and signal internal cues, such as amino acids, to coordinate cell responses. Recently, the activity of several lysosomal metabolite transporters has been elucidated, bringing new insights into lysosomal functions. Cell biological and structural studies of lysosomal transporters have also highlighted their roles in recruiting signaling complexes to lysosomes and delineated how their substrates gate such hybrid transporter/receptor, or 'transceptor', function. In this review, we summarize recent progress in our understanding of lysosomal transporters, with a focus on the export of lysosomal degradation intermediates, the existence of lysosomal amino acid shuttles that regulate the redox state and pH of the lysosomal lumen, and the role of lysosomal transceptors in nutrient and immune signaling.

Keywords: lysosomes; metabolism; signaling; transceptor; transporter

DOI: https://doi.org/10.1016/j.tcb.2025.09.004

J Cell Biol. 2026 Jan 05. pii: e202501145. [Epub ahead of print]225(1):

TMEM175 does not function as a proton-selective ion channel to prevent lysosomal over-acidification.

Erika Riederer, Vedrana Mikusevic, Tuoxian Tang, Lillian Martin, Joseph A Mindell, Dejian Ren.

The acidic pH of lysosomes required for function is established by the electrogenic V-ATPase proton pump. How lysosomes prevent hyper-acidification by the pump is not well established. Recently, the Parkinson's disease (PD)-associated protein TMEM175 was proposed as a H+-selective channel to leak protons to counter over-acidification. We rigorously address key findings and predictions of this model and show that, in the lysosome, TMEM175 predominantly conducts K+ and is not a H+-selective channel. The native lysosomal H+ leak is remarkably small, ∼0.02 fA, strongly arguing against major contributions from an ion channel. The predominant effect of TMEM175 deficiencies is lysosomal alkalinization in challenged cells, which is further evidence arguing against TMEM175 as a H+-selective channel and can be explained by K+ conductance through TMEM175. Also, lysosomes can be hyper-acidified by manipulations in the presence or absence of TMEM175. Our studies clarify a basic lysosomal biological problem and provide insights into the working mechanism of TMEM175 and its contribution to PD pathology.

DOI: https://doi.org/10.1083/jcb.202501145

PLoS One. 2025 ;20(10): e0334981

Analysis of intracellular and intercellular crosstalk from omics data.

Alice Chiodi, Paride Pelucchi, Ettore Mosca.

Disease phenotypes can be described as the consequence of interactions among molecular processes that are altered beyond resilience. Here, we address the challenge of assessing the possible alteration of intra- and inter-cellular molecular interactions among processes or cells. We present an approach, designated as "Ulisse", which complements the existing methods in the domains of enrichment analysis, pathway crosstalk analysis and cell-cell communication analysis. It applies to gene lists that contain quantitative information about gene-related alterations, typically derived in the context of omics or multi-omics studies. Ulisse highlights the presence of alterations in those components that control the interactions between processes or cells. Considering the complexity of statistical assessment of network-based analyses, crosstalk quantification is supported by two distinct null models, which systematically sample alternative configurations of gene-related changes and gene-gene interactions. Further, the approach provides an additional way of identifying the genes associated with the phenotype. As a proof-of-concept, we applied Ulisse to study the alteration of pathway crosstalks and cell-cell communications in triple negative breast cancer samples, based on single-cell RNA sequencing. In conclusion, our work supports the usefulness of crosstalk analysis as an additional instrument in the "toolkit" of biomedical research for translating complex biological data into actionable insights.

DOI: https://doi.org/10.1371/journal.pone.0334981