the effect of UMI-77 on HGPS-MSCs gene expression during cellular senescence
Hutchinson-Gilford progeria syndrome (HGPS) is a rare and fatal disease manifested by premature aging and aging-related phenotypes, making it a disease model for physiological aging. The cellular machinery mediating age-associated hallmarks in HGPS remains largely unknown, resulting in limited therapeutic targets for HGPS treatment. In this study, we showed that deficiencies in mitophagy impaired mitochondrial quality and contributed to cellular phenotypes associated with aging in mesenchymal stem cells derived from HGPS patients (HGPS-MSCs). Mechanistically, we discovered that mitophagy affected the aging-related phenotypes of HGPS-MSCs by inhibiting the cGAS-STING-NF-?B pathway and the downstream transcription of senescence-associated secretory phenotype (SASP). Furthermore, by utilizing UMI-77, an effective inducer of mitophagy, we showed that mitophagy induction can alleviate aging-associated phenotypes in both HGPS mice and naturally aged mice. In summary, our results uncover that mitophagy defects mediate mitochondrial dysfunction and aging-associated phenotypes in HGPS models, highlight the function of mitochondrial homeostasis in HGPS progression, and suggest that mitophagy could be exploited as a promising therapeutic target for both HGPS and aging. Overall design: To further elucidate how mitochondrial homeostasis affects aging phenotypes in HGPS-MSCs, we perform transcriptomic analysis on early-passage HGPS-MSCs (P3), late-passage HGPS-MSCs (P7), and UMI-77-treated late-passage (P7) HGPS-MSCs.