bims-lypmec 2026-06-14 papers

Cell Rep. 2026 Jun 08. pii: S2211-1247(26)00615-7. [Epub ahead of print]45(6): 117537

Cholesterol transfer proteins promote Atg-independent ER clearance by lysosomes.

Ruoxi Wang, Tina M Fortier, Xiaofeng Sun, Fei Chai, Panagiotis D Velentzas, Eric H Baehrecke.

Selective removal of endoplasmic reticulum (ER) is important for cell health. Macroautophagy is the primary mechanism for the removal of the ER, but the ER can be cleared in a macroautophagy-independent manner. However, the physiological relevance and mechanisms underlying macroautophagy-independent ER clearance remain largely unknown. Here we show that ER is cleared by lysosomes in a macroautophagy Atg gene-independent manner during development. This developmentally programmed Atg-independent ER clearance by lysosomes requires the ER protein Vap33 that promotes ER and lysosome contact. Oxysterol-binding protein (Osbp) is known to associate with Vap33, and Osbp lysosomal localization is required for ER clearance in cells lacking macroautophagy. Significantly, the cholesterol transport-associated protein Start1 regulates ER and lysosome contact, macroautophagy-independent ER clearance, and cholesterol transport from ER to the lysosome. These studies reveal that Vap33, Osbp, and Start1 promote ER clearance by lysosomes that is associated with cholesterol trafficking.

Keywords: CP: cell biology; Drosophila; ER; ESCRT; Osbp; Start1; Vap33; lysosome

DOI: https://doi.org/10.1016/j.celrep.2026.117537

Tissue Cell. 2026 Jun 10. pii: S0040-8166(26)00386-1. [Epub ahead of print]103 103692

VPS13C-mediated endoplasmic reticulum-lysosome tethering in neuronal stress responses.

Rabab S Hamad, Eman Hamza, Ebtehal M Abdel-Aal, Elsayed A Elmorsy, Hanan Eissa, Alshaimaa A Farrag, Ahmed Shata, Ghada M Nassar, Nesreen Elsayed Morsy, Ahmed A El-Mansy, Ahmed G Hamad, Eman R Abdellatif, Sameh Saber.

Organelle contact sites are increasingly recognized as regulatory interfaces that coordinate lipid transfer, ion signaling, and metabolic adaptation. In neurons, communication among the endoplasmic reticulum (ER), lysosomes, and mitochondria is essential for cellular homeostasis. Recent studies have identified vacuolar protein sorting 13 homolog C (VPS13C), a lipid transport protein, as a key mediator of ER-lysosome tethering and as an important component of the response to lysosomal stress. Structural analyses show that VPS13 family proteins form elongated lipid transport channels that are proposed to facilitate phospholipid transfer between adjacent membranes. Following lysosomal damage, VPS13C is recruited to ER-lysosome contact interfaces, where it forms tethering bridges that may support membrane repair by enabling high-capacity lipid transfer from the ER to lysosomal membranes. Beyond membrane repair, these contact interfaces may also participate in broader organelle communication networks. ER-lysosome contacts can occur in proximity to ER-mitochondria junctions, potentially forming multi organelle signaling hubs that coordinate lipid redistribution, calcium signaling, and mitochondrial adaptation. These signals may influence downstream responses, including activation of TFEB and TFE3, which regulate lysosomal biogenesis and autophagy. Disruption of this contact site network has emerged as a potential contributor to Parkinson's disease. Loss of VPS13C function is associated with altered lysosomal homeostasis and intersects with pathogenic pathways involving α-synuclein aggregation, PINK1/Parkin-mediated mitophagy, and LRRK2 signaling. This review presents a framework in which ER-lysosome tethering is considered part of a staged cellular damage response linking membrane repair, metabolic coordination, and transcriptional adaptation.

Keywords: ER-lysosome tethering; Lipid transfer; Lysosomal membrane repair; Organelle contact sites; Parkinson’s disease; VPS13C

DOI: https://doi.org/10.1016/j.tice.2026.103692

Curr Neuropharmacol. 2026 Jun 08.

Rejuvenating Inter-organellar Communication Via Mitophagy in Ageing and Neurodegeneration.

Katerina Kitopoulou, Antonis Roussos, Ioannis P Trougakos, Vilhelm A Bohr, Konstantinos Palikaras.

Ageing and neurodegeneration are characterized by the progressive breakdown of organellar communication between mitochondria, the endoplasmic reticulum (ER), and lysosomes. Recent findings underline mitophagy as a central modulator of this interconnected network. Impaired mitophagy induces ER fragmentation, lysosomal dysfunction, imbalanced mitochondrial dynamics, and deregulation of calcium homeostasis, suggesting that mitochondrial turnover is essential for the maintenance of global organellar architecture. Conversely, restoring mitophagy re-establishes structural integrity and functional coordination across subcellular compartments. Notably, Urolithin A (UA) rejuvenates inter-organelle crosstalk through a defined calcium-dependent mechanism. UA promotes ER-derived calcium release via ITR-1/ITPR/InsP3R, EMC-3/EMC3, and TMCO-1/TMCO1, and enhances calcium uptake into mitochondria through MCU-1/MCU. This calcium flux activates DRP-1/DRP1-mediated mitochondrial fission, facilitating mi-tophagy initiation. In parallel, calcium-dependent activation of the UNC-43/CaMKII-SKN-1/Nrf2 axis stimulates mitochondrial biogenesis and metabolic adaptation. Furthermore, UA increases ER-mitochondrial contact sites (MAMs) and restores lysosomal activity, thereby re-establishing functional inter-organellar communication in nematodes and mammalian cells. These findings establish mitophagy as a central node of cellular and tissue homeostasis, acting through the stabilization of the organellar communication network to promote healthspan and lifespan while highlighting the need for future studies to validate these mechanisms across human tissues and disease-relevant cellular contexts.

Keywords: Ageing; ER; MAMs; lysosome; mitochondria; mitophagy; neurodegeneration; urolithin A.

DOI: https://doi.org/10.2174/011570159X473929260605103158

Diabetes. 2026 Jun 06. pii: dbi260002. [Epub ahead of print]

Focusing on Diastolic Dysfunction to Achieve Consensus With the Term Diabetic Cardiomyopathy.

Alexa N King, John R Ussher.

Diabetic cardiomyopathy (DbCM) is commonly defined as ventricular dysfunction in a person living with diabetes in the absence of hypertension and/or coronary artery disease (CAD). There is increasing recognition in the field that this is a poor definition to reflect the pathology of DbCM, as many individuals with diabetes (both type 1 and type 2) are often at risk of or have coexisting hypertension or CAD. On the contrary, there is increasing evidence that people living with diabetes, particularly in the early stages of disease progression, often have asymptomatic and subclinical diastolic dysfunction. Herein, we will interrogate the clinical evidence supporting the presence of diastolic dysfunction in people living with either type 1 or type 2 diabetes in the absence of hypertension and/or CAD, and whether diastolic dysfunction should be a central feature in how we clinically define DbCM. Clinical agreement on how we define and interpret the pathology of DbCM is necessary should the field aim to develop specific pharmacotherapies for this disorder. DbCM should not be confused with heart failure with preserved ejection fraction (HFpEF), despite the latter also being characterized by diastolic dysfunction. Nonetheless, it will be imperative to understand whether DbCM can be a precursor toward the progression of HFpEF in people living with diabetes, as that may further reinforce the clinical importance of managing diastolic dysfunction in the population with diabetes.

DOI: https://doi.org/10.2337/dbi26-0002