bims-tofagi 2025-09-21 papers

Issue of 2025–09–21
two papers selected by
Michele Frison, University of Cambridge

Free Radic Biol Med. 2025 Sep 12. pii: S0891-5849(25)00977-3. [Epub ahead of print]241 150-160

Sirt1 attenuates necrotizing enterocolitis via Hif-1α deacetylation-mediated suppression of Bnip3-Dependent mitophagy.

Necrotizing enterocolitis (NEC), a life-threatening neonatal disease, involves mitochondrial dysfunction whose regulation remains unclear. This study identifies a novel Sir1/Hif-1α regulatory axis in NEC pathogenesis. We demonstrate that Sirt1 downregulation in NEC leads to Hif-1α hyperacetylation, resulting in Bnip3-mediated mitophagy activation and intestinal epithelial injury. Using clinical samples and experimental models, we show that Sirt1 downregulation correlates with mitochondrial dysfunction and intestinal barrier disruption. Pharmacological Sirt1 activation by SRT1720 effectively attenuated NEC progression through Hif-1α deacetylation and subsequent mitophagy inhibition. Importantly, we provide the first evidence that Sirt1 directly regulates Hif-1α acetylation status in intestinal epithelial cells, establishing a new molecular mechanism linking protein acetylation to mitochondrial quality control in NEC. These findings reveal Sirt1 as a master regulator of intestinal homeostasis and highlight Sirt1 activation as a promising therapeutic approach for NEC treatment.

Keywords: Acetylation; Hif-1α; Inflammation; Mitophagy; Necrotizing enterocolitis; Sirt1

DOI: https://doi.org/10.1016/j.freeradbiomed.2025.09.020

Nat Struct Mol Biol. 2025 Sep 16.

Phase separation promotes Atg8 lipidation and vesicle condensation for autophagy progression.

Yuko Fujioka, Takuma Tsuji, Tetsuya Kotani, Hiroyuki Kumeta, Chika Kakuta, Junko Shimasaki, Toyoshi Fujimoto, Hitoshi Nakatogawa, Nobuo N Noda.

Upon starvation, the autophagy-initiating Atg1 complex undergoes phase separation to organize the preautophagosomal structure (PAS) in Saccharomyces cerevisiae, from which autophagosome formation is considered to proceed. However, the physiological roles of the PAS droplet remain unclear. Here we show that core Atg proteins are recruited into early PAS droplets that are formed by phase separation of the Atg1 complex with different efficiencies in vitro. The Atg12-Atg5-Atg16 E3 ligase complex for Atg8 lipidation is the most efficiently condensed in the droplets through specific Atg12-Atg17 interaction, which is also important for the PAS targeting of the E3 complex in vivo. In vitro reconstitution demonstrates that E3-enriched early PAS droplets promote Atg8 lipidation and that Atg8 coating of the vesicle membrane is both necessary and sufficient for their condensation into the droplets. These data suggest that the PAS functions as an efficient production site for lipidated Atg8 and pools membrane seeds to drive autophagosome formation.

DOI: https://doi.org/10.1038/s41594-025-01678-3