Work

Donor‐Cell Senescence Redirects PINK1‐Marked Mitochondrial Cargo From Mitophagy to Microvesicle Transfer Through SUMO3‐Stabilized HSPA9

Year: 2026

Type: article

Abstract: Extracellular vesicle therapies have been developed for tissue repair, but how donor-cell senescence reshapes vesicle-mediated mitochondrial transfer remains unclear. Here, we show that senescent adipose-derived stem cells (ADSCs) redirect damaged mitochondria into microvesicles (MVs), converting protective vesicles into pro-degenerative carriers. Senescent ADSC-derived MVs are enriched in PINK1-marked, oxidatively damaged mitochondrial cargo. After transfer to nucleus pulposus cells (NPCs), this cargo disrupts recipient mitochondrial homeostasis, activates the cGAS-STING-NLRP3 inflammatory axis, and aggravates intervertebral disc degeneration. Proteomic and functional analyses identify HSPA9 as a mitochondrial cargo-sorting adaptor. Senescent stress induces SUMO3 conjugation of HSPA9 at K612, stabilizing HSPA9 by limiting ubiquitin-proteasomal degradation. Stabilized HSPA9 uses its peptide-binding domain to engage the kinase domain of activated PINK1 and links PINK1-positive damaged mitochondria to Annexin A1-associated MV structures. This SUMO3-HSPA9-PINK1 module diverts damaged mitochondria from PINK1-Parkin mitophagy toward MV-mediated mitochondrial transfer. Donor-cell reprogramming that restrains the release of damaged mitochondria and reinforces mitophagic clearance restores the in vivo therapeutic efficacy of senescent ADSC-derived MVs. These findings identify mitochondrial cargo fate as a switch between vesicle-mediated repair and degeneration.

Source: Advanced Science

DOI: 10.1002/advs.78392