Advanced science (Weinheim, Baden-Wurttemberg, Germany)Oct 26, 2026

Aging donor cells shift damaged mitochondria from recycling to small vesicle release using a protein-stabilizing process

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Oct 27, 2026

Abstract

Senescent adipose-derived stem cells redirect damaged mitochondria into microvesicles, converting protective vesicles into pro-degenerative carriers.

Senescent stem cells are associated with microvesicles that contain oxidatively damaged mitochondria marked by PINK1.
Transfer of these damaged mitochondria to nucleus pulposus cells disrupts their mitochondrial balance and activates inflammatory pathways.
The increase in inflammation may worsen intervertebral disc degeneration.
HSPA9 functions as a sorting adaptor for mitochondrial cargo in microvesicles, influenced by stress-induced SUMO3 modification.
Stabilized HSPA9 may divert damaged mitochondria away from degradation processes towards microvesicle-mediated transfer.
Reprogramming donor cells to limit damaged mitochondria release could restore therapeutic effects of these microvesicles.

Simplified

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.

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Aging donor cells shift damaged mitochondria from recycling to small vesicle release using a protein-stabilizing process

Abstract

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