bims-nocaut 2025-08-10 papers

Issue of 2025–08–10
four papers selected by
Quentin Frenger, University of Strasbourg

Int J Audiol. 2025 Aug 07. 1-13

An absent WD domain in the autophagy protein ATG16L1 leads to auditory and vestibular dysfunction and otoconial deficits in mice.

Robert Burkard, Sherri Jones, Timothy Jones, Yunxia Yesha Lundberg, Thomas Wileman.

OBJECTIVES: To examine the inner ear functions of mice that lack the WD domain (δWD) of autophagy protein ATG16L1.
DESIGN: Mice were assessed with vestibular evoked potentials (VsEPs), auditory brainstem responses (ABRs) and four δWD mice were observed with electron microscopy to assess otolith otoconia loss, and cochlear hair cell loss.
STUDY SAMPLE: Seven δWD mice and four control mice.
RESULTS: Compared to control mice, VsEP thresholds were elevated, latencies increased and amplitudes decreased in the δWD mice. ABR thresholds were elevated for the 32 kHz tonebursts (but not 8 or 16 kHz) in the δWD mice compared to controls. Electron microscopy in four δWD mice revealed a complete absence of otoconia in three of four otolith organs, with the remaining mouse (perhaps a failed mutant mouse, due to incomplete penetrance of this phenotype) showing a normal complement of otoconia. In the cochlea, abnormal hair cells were observed, typically showing modest hair cell loss or damage of hair cells or stereocilia.
CONCLUSIONS: Three confirmed δWD mice showed missing otoconia, and changes in VsEPs and ABRs suggest that non-canonical autophagy pathways involved in endomembrane repair and removal are important for maintaining vestibular (and perhaps auditory) function in the inner ear.

Keywords: ATG16L1; Non-canonical autophagy; auditory brainstem response; cochlear hair cells; otoconia; vestibular sensory evoked potential

DOI: https://doi.org/10.1080/14992027.2025.2539824

Biomed Pharmacother. 2025 Aug 07. pii: S0753-3322(25)00617-1. [Epub ahead of print]190 118423

Visual cycle and LC3-associated phagocytosis in retina: regulatory mechanisms and therapeutic potential.

Fanfei Liu, Qiqi Li, Yang Yang, Fang Lu.

The visual cycle plays a pivotal dual role in retina, while it's essential for maintaining vision through continuous regeneration of the light-sensitive 11-cis-retinal chromophore. Its dysregulation contributes significantly to retinal degenerative disorders including age-related macular degeneration (AMD) and Stargardt disease. Recent advances have elucidated multiple therapeutic targets in visual cycle, ranging from inhibition of enzymatic activity of RPE65 and lecithin retinol acyltransferase (LRAT) to modulation of retinoid transport proteins and enhancement of protective LC3-associated phagocytosis. Pharmacological interventions of the visual cycle demonstrate promising results in reducing toxic retinoid accumulation, though clinical application faces challenges including nyctalopia, delayed dark adaptation, and dyschromatopsia. Future research directions emphasize the need for targeted visual cycle modulators that can selectively disrupt pathological processes without compromising essential visual function. This review summarizes the visual cycle and LC3-associated phagocytosis associated with various retinal diseases, highlights recent advances in pharmacological modulation of visual cycle, and aims to provide new insights into therapeutic strategies for retinal degenerative disorders.

Keywords: LC3-associated phagocytosis; Retinal diseases; Visual cycle

DOI: https://doi.org/10.1016/j.biopha.2025.118423

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