bims-lypmec 2025-08-10 papers

Nat Rev Mol Cell Biol. 2025 Aug 04.

Lysosomal membrane homeostasis and its importance in physiology and disease.

Maja Radulovic, Chonglin Yang, Harald Stenmark.

Lysosomes are membranous organelles that are crucial for cell function and organ physiology. Serving as the terminal stations of the endocytic pathway, lysosomes have fundamental roles in the degradation of endogenous and exogenous macromolecules and particles as well as damaged or superfluous organelles. Moreover, the lysosomal membrane is a docking and activation platform for several signalling components, including mTOR complex 1 (mTORC1), which orchestrates metabolic signalling in the cell. The integrity of their membrane is crucial for lysosomes to function as hubs for the regulation of cell metabolism. Various agents, including pathogens, nanoparticles and drugs, can compromise lysosomal membrane integrity. Membrane permeabilization causes leakage of proteases and cations into the cytosol, which can induce cell death pathways and innate immunity signalling. Multiple pathways repair damaged lysosomes, and severely damaged lysosomes are degraded by an autophagic process, lysophagy. Moreover, lysosome damage activates transcriptional programmes that orchestrate lysosome biogenesis to replenish the cellular lysosome pool. In this Review, we discuss recent insights into the mechanisms that ensure the maintenance of lysosomal membrane homeostasis, including novel mechanisms of lysosomal membrane repair and the interplay between lysosome damage, repair, lysophagy and lysosome biogenesis. We highlight the importance of lysosomal membrane homeostasis in cell function, physiology, disease and ageing, and discuss the potential for therapeutic exploitation of lysosomal membrane permeabilization.

DOI: https://doi.org/10.1038/s41580-025-00873-w

J Cell Biol. 2025 Oct 06. pii: e202501007. [Epub ahead of print]224(10):

SOD1 is delivered to lysosomes via autophagy to maintain lysosomal function and integrity.

Yanzhe Zheng, Meng Li, Xuelin Chen, Ze Zheng, Zixuan Chen, Ruilin Tian, Yan G Zhao.

The gene encoding superoxide dismutase 1 (SOD1) is often mutated in familial amyotrophic lateral sclerosis (ALS), affecting motor neurons. Compared with ALS-associated mutant SOD1, the function of WT SOD1 is less explored. We demonstrate that during starvation, WT and mutant SOD1 are transported into lysosomes. Genome-wide CRISPR interference (CRISPRi) screening identified autophagy-related proteins and the autophagic receptor TP53INP1 as key mediators. TP53INP1 binds ATG8 family proteins, preferentially LC3C, and directly interacts with SOD1. Within lysosomes, SOD1 retains its enzymatic activity. Starvation induces elevated levels of lysosomal reactive oxygen species (ROS), which are further increased by knocking down SOD1 or TP53INP1. Lysosomal degradation activities and membrane integrity are also compromised in the absence of SOD1 or TP53INP1. We reveal a novel function of SOD1 in maintaining lysosomal activity and integrity, and a previously unrecognized role of autophagy in delivering cytosolic enzymes into lysosomes for catalytic purposes, rather than for degradation.

DOI: https://doi.org/10.1083/jcb.202501007

Nat Commun. 2025 Aug 07. 16(1): 7304

Impaired mitochondria-initiated crosstalk with lysosomes reciprocally aggravates mitochondrial defect through LManVI.

Shengnan Li, Zhaoliang Shan, Guochun Zhao, Yuwei Li, Minghui Du, Xiuxiu Ti, Yuxue Gao, Wenting Li, Hui Zuo, Yan Wang, Qing Zhang.

Mitochondria coordinate with lysosomes to maintain cellular homeomstasis. However, in mitochondrial defect condition, how they communicate is less clear. Here, utilizing dMterf4 RNAi fly model, we find that expression of lysosomal alpha-mannosidase VI (LManVI) is significantly downregulated. Mechanistically, we show that dMterf4 RNAi-triggered mitochondrial defect mediates downregulation of lysosomal LManVI through Med8/Tfb4-E(z)/pho axis, causing impairment of lysosomal function. Reciprocally, downregulation of lysosomal LManVI further decreases many mitochondrial genes expression through downregulation of transcriptional coactivator PGC-1, leading to aggravating the dMterf4 RNAi-mediated mitochondrial defect, suggesting that mitochondrial defect can crosstalk with lysosomes to make mitochondrial status worse in a positive feedback way. Finally, we demarcate that this interaction between mitochondria and lysosomes may be conserved in mammalian cells. Therefore, our findings unveil a communication mechanism between mitochondria and lysosomes in mitochondrial defect case, which provides insights about the treatments of related mitochondrial and lysosomal diseases through modulation of the mitochondria-lysosomes axis.

DOI: https://doi.org/10.1038/s41467-025-62147-5

Cell Signal. 2025 Aug 06. pii: S0898-6568(25)00468-1. [Epub ahead of print] 112053

Ferroptosis targeting: A novel therapeutic regimen in diabetic cardiomyopathy.

Hong Zhang, Xiudan Li.

Diabetic cardiomyopathy (DCM), one of major complication of diabetes mellitus (DM), is characterized by progressive myocardial dysfunction that occurs independently of coronary artery disease and hypertension and is accompanied by pathological cardiac remodeling. Despite its clinical significance, the molecular mechanisms driving DCM pathogenesis remain poorly understood, and current preventive and therapeutic strategies remain suboptimal. Recent advances have implicated ferroptosis, a distinct form of iron-dependent regulated cell death characterized by lipid peroxidation and dysregulated iron homeostasis, as a critical contributor to DCM development. Notably, several pharmacological agents have shown cardioprotective efficacy in DCM models by suppressing ferroptosis. In this review, we summarized the core molecular mechanisms of ferroptosis, focusing on its role in DCM pathogenesis and ferroptosis regulation during DCM progression. We then highlighted emerging therapeutic agents with ferroptosis-inhibiting activity and reviewed their beneficial pharmacological effects against DCM. Ultimately, this review underscores the potential of pharmacologically inhibiting ferroptosis as a novel therapeutic strategy for DCM.

Keywords: Bioactive compounds; Cardiomyopathy; Diabetes; Ferroptosis; Ferroptosis inhibitor

DOI: https://doi.org/10.1016/j.cellsig.2025.112053

Autophagy. 2025 Aug 03. 1-2

PDZD8 links organelle crosstalk to synaptic remodeling via autophagy.

Rajan S Thakur, Kate M O'Connor-Giles.

Synapse formation and plasticity require coordinating cellular processes from signaling to protein turnover over long distances, placing high demands on intracellular communication. Membrane contact sites (MCSs) between organelles are specialized compartments for coordinating cellular processes, yet their functions in the developing nervous system remain poorly understood. Through an in vivo CRISPR screen in Drosophila, we identified the conserved endoplasmic reticulum (ER) MCS tethering protein Pdzd8 as a regulator of activity-dependent synapse development. Our in vivo studies demonstrate that Pdzd8 functions at ER-late endosome/lysosome MCSs to promote lysosomal maturation and increase autophagic flux during periods of high demand such as prolonged neuronal activity.

Keywords: Autophagy; PDZD8; lipid transfer; lysosomes; membrane contact sites; synapse

DOI: https://doi.org/10.1080/15548627.2025.2537983