Mitophagy defect mediates the aging-associated hallmarks in Hutchinson-Gilford progeria syndrome.

Publisher: Wiley-Blackwell Country of Publication: England NLM ID: 101130839 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1474-9726 (Electronic) Linking ISSN: 14749718 NLM ISO Abbreviation: Aging Cell Subsets: MEDLINE

Publication: Oxford, UK : Wiley-Blackwell
Original Publication: Oxford, UK : Blackwell Pub., c2002-

Progeria*/metabolism ; Progeria*/genetics ; Progeria*/pathology ; Mitophagy*/genetics; Humans ; Mice ; Animals ; Aging/metabolism ; Cellular Senescence/genetics

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 aging. The cellular machinery mediating age-associated phenotypes in HGPS remains largely unknown, resulting in limited therapeutic targets for HGPS. In this study, we showed that mitophagy defects impaired mitochondrial function and contributed to cellular markers associated with aging in mesenchymal stem cells derived from HGPS patients (HGPS-MSCs). Mechanistically, we discovered that mitophagy affected the aging-associated phenotypes of HGPS-MSCs by inhibiting the STING-NF-ĸB pathway and the downstream transcription of senescence-associated secretory phenotypes (SASPs). Furthermore, by utilizing UMI-77, an effective mitophagy inducer, we showed that mitophagy induction alleviated aging-associated phenotypes in HGPS and naturally aged mice. Collectively, our results uncovered that mitophagy defects mediated the aging-associated markers in HGPS, highlighted the function of mitochondrial homeostasis in HGPS progression, and suggested mitophagy as an intervention target for HGPS and aging.
(© 2024 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

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2021YFC2700101 National Key Research and Development Program of China; 2022YFC2702300 National Key Research and Development Program of China; 32222023 National Natural Science Foundation of China; 82300800 National Natural Science Foundation of China; TD2020006 Leading innovation and entrepreneurship team of Hangzhou; BK20210150 Natural Science Foundation of Jiangsu Province; 2023C03027 Key Research and Development Program of Zhejiang Province; 2022C03005 Key Research and Development Program of Zhejiang Province; 2024SSYS0020 Key Research and Development Program of Zhejiang Province; 2021R01012 Leading Innovative and Entrepreneur Team Introduction Program of Zhejiang; LR22C070002 Natural Science Foundation of Zhejiang Province

Keywords: HGPS; UMI‐77; aging; mitophagy

Date Created: 20240314 Date Completed: 20240611 Latest Revision: 20240804

20240804

PMC11296130

10.1111/acel.14143

38482753