Donor‐Cell Senescence Redirects PINK1‐Marked Mitochondrial Cargo From Mitophagy to Microvesicle Transfer Through SUMO3‐Stabilized HSPA9
Zixuan Ou, Mingke Zhao, Zhiwei Ling, Lianqi Peng, Bide Tong, Huaizhen Liang, Hongchuan Wang, Di Wu, Yifan Du, Zhi Du, Shihao Zhang, Yuyuan Jia, Yifan Qian, Gan Xu, Liuliang He, Gang Li, Shun Zhang, Lei Tan, Kun Wang, Xiaobo Feng, Cao Yang, Zhiwei LiaoABSTRACT
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.