bims-raghud 2025-12-07 papers

Nat Commun. 2025 Dec 03. 16(1): 10858

Development of a p62 biodegrader for autophagy targeted degradation.

Autophagy-based targeted degradation offers a powerful complement to proteasomal degradation leveraging the capacity and versatility of lysosomes to degrade complex cargo. However, it remains unclear which components of the autophagy-lysosomal pathway are most effective for targeted degradation. Here, we describe two orthogonal induced-proximity strategies to identify autophagy effectors capable of degrading organelles and soluble targets. Recruitment of autophagy cargo receptors, ATG8-like proteins, or the kinases ULK1 and TBK1 is sufficient to trigger mitophagy, while only autophagy cargo receptors capable of self-oligomerization degrade soluble cytosolic proteins. We further report a single-domain antibody against p62 and its use as a heterobifunctional degrader to clear mitochondria. Fusing the p62 single-domain antibody to PINK1 enables selective targeting of damaged mitochondria. Our study highlights the importance of avidity for targeted autophagy and suggests that autophagy cargo receptors are attractive entry points for the development of heterobifunctional degraders for organelles or protein aggregates.

DOI: https://doi.org/10.1038/s41467-025-65868-9

Mol Metab. 2025 Dec 02. pii: S2212-8778(25)00199-1. [Epub ahead of print] 102292

Reprogramming of cholesterol sensing in epithelial cells supports pancreatic inflammation.

Giulia Milan, Olga A Mareninova, Marco Fantuz, Martina Spacci, Carlotta Paoli, Jerik A Pineda, Roberta Noè, Beatrice Calciolari, Roberto Zoncu, Anna S Gukovskaya, Alessandro Carrer.

Pancreatitis is a common cause of hospitalization that necessitates attentive clinical management. Affected individuals are at risk for pancreatic cancer due to aberrant signaling and empowered cell plasticity. Yet, molecular and cellular dynamics that govern epithelial cell behavior in response to inflammation remain largely elusive. Here we found that inflammation induces Endoplasmic Reticulum-Associated Degradation protein (ERAD)-mediated downregulation of Niemann-Pick type C protein 1 (NPC1), which leads to the sequestration of free cholesterol within acinar cells' lysosomes. Reducing intra-pancreatic cholesterol levels through genetic ablation of Acly ameliorates cerulein-induced pancreatitis, while pharmacological targeting of NPC1 exacerbates tissue damage. Mechanistically, the accumulation of lysosomal cholesterol is sensed by the mechanistic Target of Rapamycin Complex 1 (mTORC1) that promotes metaplasia of pancreatic acinar cells, an event commonly associated to pancreatitis and tissue regeneration. Indeed, cholesterol supplementation or NPC1 inhibition facilitate acinar-to-ductal metaplasia (ADM) both ex vivo and in vivo, in an mTORC1-dependent manner. These results identify a metabolic/signaling axis driving the reprogramming of pancreatic epithelial cells in response to inflammation. This hinges on a nutrient sensing paradigm, previously documented exclusively in pathological conditions.

Keywords: acinar-to-ductal metaplasia (ADM); cholesterol; lysosome; mTORC1; pancreatitis

DOI: https://doi.org/10.1016/j.molmet.2025.102292

Life Sci. 2025 Nov 29. pii: S0024-3205(25)00763-5. [Epub ahead of print]385 124127

Mitochondria at the crossroads of aging and cardiovascular disease.

Olubodun Michael Lateef, Sodiq Fakorede, Chanel Harris, Adeola Mariam Lateef, Ayodeji Folorunsho Ajayi.

Mitochondrial dysfunction plays a critical role in cardiovascular aging and is a key player in the development of cardiovascular diseases (CVDs) such as hypertension, arteriosclerosis, aneurysms, and heart failure. Aging disrupts mitochondrial function through impaired oxidative phosphorylation, excessive reactive oxygen species generation, mitochondrial DNA mutations, endoplasmic reticulum stress, mitochondrial enzyme dysregulation, and impaired calcium homeostasis. These alterations drive endothelial dysfunction, arterial stiffening, cardiac remodeling, and ultimately exacerbate age-related cardiovascular decline. Despite extensive research, the precise mechanisms by which mitochondrial aging impairs the function of endothelial cells, vascular smooth muscle cells, and cardiomyocytes remain poorly understood. Therefore, this review synthesizes current evidence on how aging-associated mitochondrial dysfunction contributes to endothelial dysfunction, arterial stiffening and remodeling, and cardiac dysfunction. It also outlines emerging pathophysiological mechanisms linking mitochondrial dysfunction to age-related CVDs, offering insights into potential therapeutic targets to promote cardiovascular health in aging populations. This review highlights key biomarkers of declining mitochondrial function to facilitate early diagnosis of CVD-related mitochondrial dysfunction. We show that aging disrupts key regulators of mitochondrial dynamics and quality control in the vasculature and heart across human studies and preclinical models of aging. Recent evidence indicates that impaired mitochondrial function in aging cardiomyocytes results in valvular degeneration, left ventricular hypertrophy, diastolic dysfunction, atrial fibrillation, and diminished exercise capacity. Therefore, understanding the pathophysiological mechanisms linking mitochondrial dysfunction to cardiovascular aging may guide the development of new therapeutic strategies for mitigating age-related cardiovascular decline in older adults.

Keywords: Arterial disease; Cardiomyopathy; Cardiovascular aging; Endothelial dysfunction; Mitochondrial dysfunction

DOI: https://doi.org/10.1016/j.lfs.2025.124127

Proc Natl Acad Sci U S A. 2025 Dec 09. 122(49): e2512046122

Control of renal calcium permeability via a tight junctional claudin switch.

Rozemarijn E van der Veen, Marie Bieck, Nacéra Mezouar, Volker Haucke, Henrik Dimke, Martin Lehmann.

Tight junctions seal the paracellular space between epithelial cells, with their claudin (CLDN) composition dictating epithelial permeability properties. In kidney thick ascending limbs, calcium is reabsorbed paracellularly through a meshwork of CLDN16 and CLDN19 polymers. CLDN14 is strongly upregulated by high blood calcium, restricts this paracellular calcium flux, and is linked to kidney stone disease. How CLDN14 controls paracellular calcium flux and structurally incorporates into this complex junction is unknown. Using confocal and super-resolution microscopy, we show that CLDN14 preferentially associates with CLDN19, thereby gradually replacing CLDN16 in the CLDN19 copolymer in vitro and in mice in vivo. The claudin switch depends on CLDN14 polymerization and occurs on a timescale of days via a pathway independent of dynamin-mediated endocytosis. Our findings reveal a mechanism of tight junction regulation, demonstrating how dynamic claudin remodeling within this complex structure controls renal calcium excretion and contributes to kidney stone pathogenesis.

Keywords: Claudins; kidney stone disease; paracellular calcium transport; super-resolution microscopy; tight junction

DOI: https://doi.org/10.1073/pnas.2512046122

Nat Cell Biol. 2025 Dec 03.

A human epiblast model reveals dynamic TGFβ-mediated control of epithelial identity during mammalian epiblast development.

Pluripotency, the ability to generate all body cell types, emerges in a disorganized embryonic cell mass. After implantation, these cells form a columnar epithelium and initiate lumenogenesis. During gastrulation, some undergo epithelial-to-mesenchymal transition to form the primitive streak (PS). The signals controlling these events in humans are largely unknown. Here, to study them, we developed a chemically defined 3D model where conventional pluripotent stem cells self-organize into a columnar epithelium with a lumen, from which PS-like cells emerge. We show that early TGFβ family inhibition prevents epithelial identity, also in murine 3D embryo models and in embryos. ZNF398 acts downstream of TGFβ1, activating the epithelial master regulator ESRP1 while repressing mesenchymal factors CDH2 and ZEB2. After epithelium formation, TGFβ1 stimulation is dispensable for its maintenance. However, treatment via ACTIVIN-a distinct TGFβ family ligand-induces PS efficiently. Thus, signalling of the TGFβ family dynamically governs pluripotent epiblast epithelial identity.

DOI: https://doi.org/10.1038/s41556-025-01831-6