Zinc influx promotes mitophagy to slow intervertebral disc degeneration

In cellular and in vivo models of intervertebral disc degeneration, researchers investigated how senescence-related ion imbalances suppress autophagy. By combining single-cell RNA sequencing, messenger RNA sequencing, and mass spectrometry, the team identified the zinc transporter ZIP14 as a central regulatory factor. They found that intracellular zinc drives the deacetylation of annexin A2 at lysine 302. In vitro mutagenesis and molecular dynamics simulations showed that this deacetylation alters the annexin A2-mTOR complex and prevents annexin A2 from binding mTOR, thereby restoring mitophagy. Acetylated annexin A2 accumulated abnormally during disease development and restrained mitophagy. In vivo experiments confirmed that ZIP14 sustains this protective signaling, and dietary zinc supplementation effectively slowed disc degeneration.