bims-lypmec 2026-05-10 papers

EMBO J. 2026 May 02.

Peroxisome-derived ether lipids regulate lysosomal exocytosis.

Liang Chen, Danielle Henn, Zhongzheng Dong, Jiaxuan Liang, Aleksander Wielenga, Goncalo Vale, Bala Burugula, Junyi Zou, Yamuna Krishnan, Jeffrey G McDonald, Jacob Kitzman, Ming Li.

Lysosomes and peroxisomes are essential for cellular homeostasis, yet how their activities are coordinated remains poorly understood. Here, we identify peroxisome-derived ether lipids as key regulators of lysosomal function. A genome-wide CRISPR/Cas9 screen in LYSET-deficient mucolipidosis V cells revealed that disruption of ether lipid synthesis genes or peroxins markedly reduces lysosome accumulation and restores degradative capacity. Genetic or pharmacological inhibition of ether lipid synthesis enhanced lysosomal exocytosis and promoted the clearance of undigested material independently of mannose-6-phosphate trafficking. Conversely, supplementation with the ether lipid precursor hexadecylglycerol increased lysosome abundance, while reducing their degradative capacity. These findings uncover a peroxisome-lysosome metabolic axis, in which ether lipids act as bidirectional regulators of lysosomal number and function independently of the lysosomal master regulator TFEB. Our findings reveal how peroxisome-localized lipid metabolism modulates lysosomal homeostasis, and suggest potential new strategies to combat lysosomal and peroxisomal disorders.

DOI: https://doi.org/10.1038/s44318-026-00791-3

Autophagy. 2026 May 06. 1-3

When tau stalls the lysosome: decoupling trafficking and degradation in autophagy.

Celeste M Karch, Farzaneh S Mirfakhar.

Tauopathies are characterized by the accumulation of misfolded tau and lysosomal dysfunction, yet whether defects in the autophagy-lysosome pathway are causal or secondary remains unclear. Recent work using human iPSC-derived neurons harboring the MAPT p.R406W mutation demonstrates that pathogenic tau is sufficient to disrupt lysosomal function upstream of tau accumulation. Tau species are differentially processed within lysosomes, with phosphorylated tau retained at the lysosomal membrane, consistent with a barrier to efficient cargo processing. Importantly, pharmacologic activation of autophagy restores degradative capacity and reduces tau burden without rescuing lysosomal motility, suggesting that trafficking and degradation represent separable axes of lysosomal biology. These findings position tau as an active disruptor of proteostasis and define a degradative bottleneck that shares features with lysosomal storage disorders. Together, this work reframes autophagy dysfunction in tauopathy as a modular defect with distinct therapeutic entry points.

Keywords: Induced pluripotent stem cells; MAPT; lysosomal trafficking; neurons; tauopathy

DOI: https://doi.org/10.1080/15548627.2026.2669685

Autophagy. 2026 May 05.

RYR:ATP6V0A1 complexes couple ER-lysosome contact sites to dynamic autophagy control.

Jens Loncke, Manon Callens, Geert Bultynck, Tim Vervliet.

Ryanodine receptors (RYRs) are ER-resident Ca2 + -release channels enriched in excitable cells, including neurons. RYR hyperactivity is implicated in early pathogenesis of disorders such as Alzheimer's disease (AD), which is associated with impaired autophagy. We recently uncovered a mechanism linking RYR activity to lysosome availability for autophagy. RYRs localize to ER - lysosome contact sites via direct binding to ATP6V0A1, a V-ATPase subunit that also suppresses RYR-mediated Ca2 + release. In human iPSC-derived cortical neurons, spontaneous RYR activity promotes lysosomal secretion, depleting the intracellular lysosomal pool and inhibiting autophagic flux. RYR inhibition promotes ER - lysosome contacts, limits lysosomal secretion, and restores lysosome availability for autophagosome fusion and cargo degradation (including APP). Conversely, disrupting the RYR:ATP6V0A1 interaction using a RYR-derived protein fragment serving as a "decoy" for ATP6V0A1 evokes RYR hyperactivity and stimulates lysosomal secretion. In this Punctum, we discuss how this RYR2:ATP6V0A1 "contact-site hub" may be perturbed in disease and highlight open questions on how lysosomes decode RYR-derived Ca2 + signals.

Keywords: Calcium signaling; V-type ATPase; endoplasmic reticulum; lysosome; membrane contact site; ryanodine receptor

DOI: https://doi.org/10.1080/15548627.2026.2669981

FEBS Lett. 2026 May 03.

pH-mediated activation of the lysosomal arginine sensor SLC38A9.

Xuelang Mu, Ampon Sae Her, Tamir Gonen.

Cells rely on metabolic control; the mechanistic target of rapamycin complex 1 (mTORC1) senses nutrient availability, particularly amino acids. Lysosomes maintain amino acid homeostasis through recycling. SLC38A9, a lysosomal amino acid transporter, functions as a critical sensor in the mTORC1 pathway. Here, we investigate how pH regulates SLC38A9 activity. We show that arginine uptake is pH-dependent, with His544 residue serving as the pH sensor. Mutating His544 abolishes pH dependence without impairing overall transport, indicating His544 influences transport through protonation/deprotonation, instead of involving in the substrate binding. We propose a working model for pH-induced activation, through comparing two determined SLC38A9 structures at different pH. These findings reveal how local ionic shifts regulate lysosomal transporters and fine-tune SLC38A9 function to control mTORC1 signaling.

Keywords: SLC family; amino acid transport; mTOR complex; pH‐regulation; transceptor

DOI: https://doi.org/10.1002/1873-3468.70352

J Diabetes Res. 2026 ;2026(1): e7460084

Heart Failure in Type 1 vs. Type 2 Diabetes Mellitus: Shared Pathways, Distinct Challenges.

Muhammad S Hussain, Saraswathi Iyer, Yi Jia Liew, Mya Lelt Win, Rory J McCrimmon, Chim C Lang, Ify R Mordi.

Heart failure (HF) is a critical complication in both type 1 (T1D) and type 2 diabetes (T2D) and people with diabetes are at higher risk of developing HF than those without diabetes. The pathophysiology of HF in diabetes often involves diabetic cardiomyopathy, driven by insulin deficiency, insulin resistance (IR), inflammation, and myocardial fibrosis; however, though there are similarities in HF in T1D and T2D, there are also key differences in epidemiology, pathophysiology, treatment, and clinical outcomes. In this review article we will discuss the burden, pathophysiology, and outcomes of HF in diabetes, focusing on differences between T1D and T2D, and the relative unmet need for patients with T1D and HF.

Keywords: GLP-1RA and finerenone; HFpEF; HFrEF; SGLT-2i inhibitors and Sotagliflozin; cardiac microvascular dysfunction (CMD); heart failure (HF); type 1 diabetes (T1D); type 2 diabetes (T2D)

DOI: https://doi.org/10.1155/jdr/7460084