Donor‐Cell Senescence Redirects PINK1‐Marked Mitochondrial Cargo From Mitophagy to Microvesicle Transfer Through SUMO3‐Stabilized HSPA9
- 1Department of Orthopaedics Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan People's Republic of China
- 2Department of Dermatology Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan People's Republic of China
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.
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BibTeX
@article{ou2026donorcell,
title = {{Donor‐Cell Senescence Redirects PINK1‐Marked Mitochondrial Cargo From Mitophagy to Microvesicle Transfer Through SUMO3‐Stabilized HSPA9}},
author = {Zixuan Ou and Mingke Zhao and Zhiwei Ling and Lianqi Peng and Bide Tong and Huaizhen Liang and Hongchuan Wang and Di Wu and Yifan Du and Zhi Du and Shihao Zhang and Yuyuan Jia and Yifan Qian and Gan Xu and Liuliang He and Gang Li and Shun Zhang and Lei Tan and Kun Wang and Xiaobo Feng and Cao Yang and Zhiwei Liao},
journal = {Advanced Science},
year = {2026},
month = oct,
doi = {10.1002/advs.78392},
url = {https://doi.org/10.1002/advs.78392},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Donor‐Cell Senescence Redirects PINK1‐Marked Mitochondrial Cargo From Mitophagy to Microvesicle Transfer Through SUMO3‐Stabilized HSPA9
AU - Zixuan Ou
AU - Mingke Zhao
AU - Zhiwei Ling
AU - Lianqi Peng
AU - Bide Tong
AU - Huaizhen Liang
AU - Hongchuan Wang
AU - Di Wu
AU - Yifan Du
AU - Zhi Du
AU - Shihao Zhang
AU - Yuyuan Jia
AU - Yifan Qian
AU - Gan Xu
AU - Liuliang He
AU - Gang Li
AU - Shun Zhang
AU - Lei Tan
AU - Kun Wang
AU - Xiaobo Feng
AU - Cao Yang
AU - Zhiwei Liao
PY - 2026
DA - 2026/10/25
JO - Advanced Science
DO - 10.1002/advs.78392
UR - https://doi.org/10.1002/advs.78392
AB - 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.
SN - 2198-3844
ER -