bims-tofagi 2025-08-10 papers

Issue of 2025–08–10
two papers selected by
Michele Frison, University of Cambridge

Nat Cell Biol. 2025 Aug 04.

The intrinsically disordered regions of organellophagy receptors are interchangeable and control organelle fragmentation, ER-phagy and mitophagy flux.

Mikhail Rudinskiy, Carmela Galli, Andrea Raimondi, Maurizio Molinari.

Organellophagy receptors control the generation and delivery of portions of their homing organelle to acidic degradative compartments to recycle nutrients, remove toxic or aged macromolecules and remodel the organelle upon physiologic or pathologic cues. How they operate is not understood. Here we show that organellophagy receptors are composed of a membrane-tethering module that controls organellar and suborganellar distribution and by a cytoplasmic intrinsically disordered region (IDR) with net cumulative negative charge that controls organelle fragmentation and displays an LC3-interacting region (LIR). The LIR is required for lysosomal delivery but is dispensable for organelle fragmentation. Endoplasmic reticulum (ER)-phagy receptors' IDRs trigger DRP1-assisted mitochondrial fragmentation and mitophagy when transplanted at the outer mitochondrial membrane. Mitophagy receptors' IDRs trigger ER fragmentation and ER-phagy when transplanted at the ER membrane. This offers an interesting example of function conservation on sequence divergency. Our results imply the possibility to control the integrity and activity of intracellular organelles by surface expression of organelle-targeted chimeras composed of an organelle-targeting module and an IDR module with net cumulative negative charge that, if it contains a LIR, eventually tags the organelle portions for lysosomal clearance.

DOI: https://doi.org/10.1038/s41556-025-01728-4

Redox Biol. 2025 Jul 31. pii: S2213-2317(25)00306-4. [Epub ahead of print]86 103793

Arylsulfatase K attenuates airway epithelial cell senescence in COPD by regulating parkin-mediated mitophagy.

Ruonan Yang, Yuan Zhan, Zhesong Deng, Jiaheng Zhang, Shanshan Chen, Yating Zhang, Hao Fu, Xiangling Meng, Jixing Wu, Yiya Gu, Qian Huang, Congyi Wang, Jungang Xie.

Chronic obstructive pulmonary disease (COPD) is a heterogeneous lung condition characterized by irreversible airflow limitation, primarily due to cigarette smoke (CS) exposure. Emerging research underscores the pivotal role of cellular senescence in the pathogenesis of COPD. The arylsulfatase family, known for its involvement in various age-related diseases, has yet to be investigated in the context of COPD. This study investigated the role of the arylsulfatase family, particularly ARSK, in COPD pathogenesis. Bioinformatics analysis and clinical validation revealed significantly reduced ARSK expression in COPD patients' lungs, especially in airway epithelium. ARSK overexpression alleviated CS-induced epithelial cellular senescence and improved mitophagy and mitochondrial function, while ARSK knockdown had an opposite effect. In vivo, Arsk-AAV administration relieved lung senescence and impaired lung function upon CS exposure, whereas airway-specific Arsk knockout aggravated these effects. Mechanistically, ARSK interacted with Parkin (PRKN) to regulate the phosphorylation of PRKN at serine 65 and subsequent mitophagy, thus attenuating cellular senescence. Additionally, the androgen receptor (AR) was identified as a transcription factor binding to the ARSK promoter, modulating its expression. These findings highlight the protective role of ARSK against epithelial cellular senescence, offering a potential therapeutic target for COPD.

Keywords: Airway epithelial cell senescence; Arylsulfatase K; Chronic obstructive pulmonary disease; Cigarette smoke; Mitophagy

DOI: https://doi.org/10.1016/j.redox.2025.103793