Mitophagy maintains tissue homeostasis by self-eliminating defective mitochondria through autophagy.How mitophagy regulates stem cell activity during hair regeneration remains unclear.Here,we found that mitophagy prom...Mitophagy maintains tissue homeostasis by self-eliminating defective mitochondria through autophagy.How mitophagy regulates stem cell activity during hair regeneration remains unclear.Here,we found that mitophagy promotes the proliferation of hair germ(HG)cells by regulating glutathione(GSH)metabolism.First,single-cell RNA sequencing,mitochondrial probe,transmission electron microscopy,and immunofluorescence staining showed stronger mitochondrial activity and increased mitophagy-related gene especially Prohibitin 2(Phb2)expression at early-anagen HG compared to the telogen HG.Mitochondrial inner membrane receptor protein PHB2 binds to LC3 to initiate mitophagy.Second,molecular docking and functional studies revealed that PHB2-LC3 activates mitophagy to eliminate the damaged mitochondria in HG.RNA-seq,single-cell metabolism,immunofluorescence staining,and functional validation discovered that LC3 promotes GSH metabolism to supply energy for promoting HG proliferation.Third,transcriptomics analysis and immunofluorescence staining indicated that mitophagy was down-regulated in the aged compared to young-mouse HG.Activating mitophagy and GSH pathways through small-molecule administration can reactivate HG cell proliferation followed by hair regeneration in aged hair follicles.Our findings open up a new avenue for exploring autophagy that promotes hair regeneration and emphasizes the role of the self-elimination effect of mitophagy in controlling the proliferation of HG cells by regulating GSH metabolism.展开更多
基金supported by the National Key Research and Development Program of China(2023YFC2508200)the National Natural Science Foundation of China(82373509,82003384,and 82203960)+5 种基金Fundamental Research Funds for the Central Universities(2022CDJYGRH-003 and 2023CDJKYJH066)the Natural Science Foundation of Chongqing(CSTB2023JXJL-YFX0028)Chongqing Talents:Exceptional Young Talents Project(cstc2021ycjh-bgzxm0197)Inheritance and Innovation Team of TCM Treatment of Immune Diseases,Scientific Research Foundation from Chongqing University(02210011044110)Research Horizontal Projects of Chongqing University(H20231432 and H20230936),ChinaC.-M.C.is supported by a research contract(GR1035751)between USC and CMU and US NIH grant R37 AR060306.
文摘Mitophagy maintains tissue homeostasis by self-eliminating defective mitochondria through autophagy.How mitophagy regulates stem cell activity during hair regeneration remains unclear.Here,we found that mitophagy promotes the proliferation of hair germ(HG)cells by regulating glutathione(GSH)metabolism.First,single-cell RNA sequencing,mitochondrial probe,transmission electron microscopy,and immunofluorescence staining showed stronger mitochondrial activity and increased mitophagy-related gene especially Prohibitin 2(Phb2)expression at early-anagen HG compared to the telogen HG.Mitochondrial inner membrane receptor protein PHB2 binds to LC3 to initiate mitophagy.Second,molecular docking and functional studies revealed that PHB2-LC3 activates mitophagy to eliminate the damaged mitochondria in HG.RNA-seq,single-cell metabolism,immunofluorescence staining,and functional validation discovered that LC3 promotes GSH metabolism to supply energy for promoting HG proliferation.Third,transcriptomics analysis and immunofluorescence staining indicated that mitophagy was down-regulated in the aged compared to young-mouse HG.Activating mitophagy and GSH pathways through small-molecule administration can reactivate HG cell proliferation followed by hair regeneration in aged hair follicles.Our findings open up a new avenue for exploring autophagy that promotes hair regeneration and emphasizes the role of the self-elimination effect of mitophagy in controlling the proliferation of HG cells by regulating GSH metabolism.
