bims-lypmec 2026-05-31 papers

EMBO J. 2026 May 29.

The C9orf72/SMCR8 complex maintains microglial homeostasis via RAB8A ESCRT-mediated lysosomal repair.

Shan Li, Shidong Xu, Feng Li, Qirui Zhao, Penghui Zhang, Qinghua Guan, Xiangxiang Sun, Jundong Bi, Hu Xiao, Yiyuli Tang, Cheng Peng, Qingfeng Chen, Yonghua Wang, Mei Yang.

Microglia are critical regulators of neuroinflammation and neurodegeneration. Haploinsufficiency of C9orf72, the most frequently mutated gene in amyotrophic lateral sclerosis and frontotemporal dementia, has been linked to autophagy-lysosomal pathway defects, but the role of C9orf72 in microglia remains unclear. Here, we identify the C9orf72/SMCR8 complex as a key regulator of microglial homeostasis through promoting lysosomal membrane repair. Loss of C9orf72 and SMCR8 in mice causes age‑dependent neuroinflammation and microgliosis, with microglia adopting a disease-associated state. In aged brain and spinal cord tissue, microglia display lysosomal damage marked by galectin‑3 accumulation. Using a lysosomotropic agent to induce lysosomal damage in microglia, we find that C9orf72/SMCR8-deficient cells accumulate damaged lysosomes and show defective recruitment of phosphorylated RAB8A and the Endosomal Sorting Complexes Required for Transport (ESCRT) machinery to damaged lysosomes. Notably, mutant microglia accumulate GTP‑bound RAB8A, which becomes hyperphosphorylated and mislocalized to RAB7-positive, LAMP1-negative vesicles. The GTPase-activating activity of the C9orf72/SMCR8 complex is essential for lysosomal repair. Our findings reveal that the C9orf72/SMCR8 complex coordinates RAB8A-ESCRT-mediated lysosomal repair to safeguard microglial homeostasis and limit neuroinflammation.

DOI: https://doi.org/10.1038/s44318-026-00817-w

Autophagy. 2026 May 25.

Mammalian Lysophagy: mechanisms and pathophysiological implications.

Fujian Ji, Mingran Dai, Zimu Wang, Enyong Dai, Rui Kang, Daniel J Klionsky, Daolin Tang, Yan Huang, Yu Sun, Liu Tong.

Lysophagy is a form of selective macroautophagy/autophagy that preserves lysosomal integrity by eliminating damaged lysosomes. Lysosomal membrane permeabilization can arise from diverse physiological and pathological insults, including proteotoxic stress, crystalline particles, pathogens and chemical perturbations, and occurs along a continuum ranging from transient nanoscale lesions to catastrophic rupture. Cells respond to lysosomal injury through a hierarchical quality-control network in which membrane repair, lysophagic removal and lysosomal regeneration operate in a coordinated manner. Damage recognition involves sensing of exposed lumenal glycans and membrane lipids, followed by ubiquitin-dependent tagging that recruits selective autophagy receptors and activates the core autophagy machinery to form lysophagosomes. Lysophagy is closely integrated with membrane repair pathways, metabolic signaling and innate immune responses that together determine lysosomal fate. Dysregulated lysosomal quality control has been implicated in diverse diseases, including neurodegeneration, infection, cancer and chronic inflammatory disorders. In this review, we summarize current mechanistic insights and emerging experimental approaches for studying lysosomal quality control and lysophagy in mammalian cells.

Keywords: Autophagy receptor; disease; lysophagy; lysosomes; repair

DOI: https://doi.org/10.1080/15548627.2026.2679642

Nat Commun. 2026 May 27. pii: 4602. [Epub ahead of print]17(1):

A PI(3,5)P2/CHMP4B axis on lysosomes is essential for microautophagic degradation of STING.

Stimulator of interferon genes (STING) is critical for the type I interferon responses to pathogen- or self-derived cytosolic DNA. STING signalling is terminated by ESCRT-driven lysosomal microautophagy. How STING is directly encapsulated by lysosomes has not yet been understood. Here we show that two lysosomal components, a phosphoinositide PI(3,5)P2 and CHMP4B (a subunit of ESCRT-III subcomplex) are essential for STING encapsulation by lysosomes. Liposome sedimentation assay reveals that CHMP4B binds to PI(3,5)P2. The forced recruitment of the catalytic core of Pikfyve (a lipid kinase generating PI(3,5)P2) to early endosomes, recruits a fraction of CHMP4B to early endosomes. CHMP4B mutant, defective in the binding to PI(3,5)P2, cannot restore the microautophagic degradation of STING or the resolution of the STING signalling in cells depleted of Chmp4b. Our results reveal a molecular mechanism that terminates innate immune signalling at the lysosomal membrane.

DOI: https://doi.org/10.1038/s41467-026-72828-4

Mol Cell. 2026 May 29. pii: S1097-2765(26)00310-2. [Epub ahead of print]

Mitochondria-lysosome coupling contributes to lysosome acidification and aging.

Qingqing Liu, Seungmin Yoo, Zhixin A Zhang, Liying Li, Hetian Su, Lingraj Vannur, Alexandra C Wooldredge, Jun-Wei B Hughes, Pierre-Yves Desprez, Nan Hao, Gordon Lithgow, Julie K Andersen, Malene Hansen, Judith Campisi, Chuankai Zhou.

Nearly all cellular processes are pH dependent. The acidic pH inside the lysosome (vacuole in yeast) is essential for cellular content degradation, signaling, and autophagy. Defects in lysosome/vacuole acidification are a conserved hallmark of aging and age-related diseases. Traditionally, the lysosome/vacuole is thought to import free protons (H⁺) from the surrounding neutral cytosol. Here, we uncovered a conserved lysosome/vacuole acidification mechanism from yeast to human involving lysosomal/vacuolar uptake of H+ pumped out by mitochondrial electron transport chain through mitochondria-lysosomes/vacuoles membrane contacts. Aging/senescence-associated disruption of mitochondria-lysosome/vacuole contacts causes lysosomal/vacuolar de-acidification, which can be reversed by either expressing an engineered linker to connect these two organelles or through an asymmetry-dependent rejuvenation process in daughter cells. Preserving lysosomal acidification in senescent human cells prevents the induction of major senescence-associated secretory phenotype factors and restores autophagic flux. These findings reshape our current understanding of the mechanisms underlying lysosomal/vacuolar (de-)acidification in both young and aged/senescent cells.

Keywords: Mito-Vac/Lyso contacts; SASP; aging; autophagy; cellular senescence; mitochondria; proton; vacuolar/lysosomal acidification

DOI: https://doi.org/10.1016/j.molcel.2026.05.004

Biomed Pharmacother. 2026 May 28. pii: S0753-3322(26)00595-0. [Epub ahead of print]200 119559

Mitochondrial metabolic reprogramming in diabetic cardiomyopathy.

Yuting Zhou, Hao Tian, Zhongyuan Xia, Yonghong Xiong.

Diabetes mellitus represents a major global health challenge and is strongly associated with cardiovascular complications, among which diabetic cardiomyopathy (DCM) is a major contributor to heart failure. Increasing evidence indicates that mitochondrial dysfunction plays a central role in DCM pathogenesis. However, mitochondrial abnormalities in the diabetic heart reflect not merely cellular injury but a coordinated process of mitochondrial metabolic reprogramming, characterized by altered substrate utilization, impaired oxidative phosphorylation, and disruption of mitochondrial quality control. Under diabetic conditions, chronic hyperglycemia, insulin resistance, and lipid overload induce profound metabolic remodeling in cardiomyocytes. These disturbances promote excessive reactive oxygen species production, mitochondrial DNA damage, and dysfunction of the electron transport chain. Concurrently, cardiomyocytes undergo a shift in substrate preference, including enhanced glycolysis, dysregulated fatty acid oxidation, and altered amino acid metabolism. Such metabolic inflexibility compromises ATP production and contributes to lipotoxicity, oxidative stress, and cardiomyocyte apoptosis. Recent studies have revealed that mitochondrial metabolic reprogramming is governed by complex regulatory networks, including signaling pathways such as AMPK/PGC-1α, PI3K/Akt/mTOR, hypoxia-inducible factor-1α, and TGF-β/Smad, together with epigenetic mechanisms and mitochondrial quality control processes. Disruption of mitochondrial dynamics, mitophagy, and mitochondrial biogenesis further promotes the accumulation of dysfunctional mitochondria and accelerates disease progression. In this review, we summarize current advances in the mechanisms underlying mitochondrial metabolic reprogramming in diabetic cardiomyopathy and discuss emerging therapeutic strategies targeting mitochondrial metabolism. By integrating mitochondrial biology with cardiovascular metabolism, this review provides a comprehensive framework for understanding DCM pathogenesis and highlights potential directions for precision therapeutic intervention.

Keywords: Diabetic cardiomyopathy; Mitochondrial metabolic reprogramming; Mitochondrial quality control; Oxidative phosphorylation; Substrate utilization

DOI: https://doi.org/10.1016/j.biopha.2026.119559

Antioxidants (Basel). 2026 May 13. pii: 618. [Epub ahead of print]15(5):

Regulation of Ferroptosis Sensitivity in Hepatocellular Carcinoma Cells by Lysosomal Ion Channels TPC2 and TRPML1.

Franz Geisslinger, Victoria Gell, Finja Witt, Dawid Jaślan, Christian Grimm, Andreas Koeberle, Karin Bartel.

Ferroptosis is an iron-dependent, lipid peroxidation-driven form of regulated cell death that has emerged as a therapeutic vulnerability in hepatocellular carcinoma (HCC), yet the contribution of lysosomes to this process remains incompletely understood. In this study, we investigated whether lysosomal ion channels regulate ferroptosis sensitivity in HCC cells, focusing on the two-pore channel 2 (TPC2) and the transient receptor potential mucolipin 1 (TRPML1). Using pharmacological modulation, genetic knockout models, flow cytometry-based cell death and lipid peroxidation assays, lipidomics, calcium measurements, and molecular analyses across multiple HCC cell lines, we examined how these channels influence ferroptotic signaling. We show that NAADP-dependent TPC2 activity is required for efficient ferroptosis induction, whereas TPC2 loss renders HCC cells resistant to ferroptosis triggered by system Xc- inhibition or glutathione peroxidase 4 (GPX4)blockade. This resistance is associated with reduced lipid peroxidation, altered calcium signaling, and selective depletion of polyunsaturated phosphatidylethanolamine species linked to decreased Acyl-CoA Synthetase Long-Chain Family Member 4 (ACSL4) expression. In contrast, TRPML1 deficiency sensitizes cells to ferroptosis and correlates with enhanced endoplasmic reticulum stress and oxidative imbalance rather than major lipid remodeling. Collectively, these findings identify lysosomal ion channels as key modulators of ferroptosis in HCC and highlight distinct mechanisms by which TPC2 and TRPML1 regulate cellular redox balance and death susceptibility.

Keywords: ACSL4; TPC2; TRPML1; calcium signaling; ferroptosis; hepatocellular carcinoma; lipid peroxidation; lysosomes; oxidative stress; redox biology

DOI: https://doi.org/10.3390/antiox15050618