IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-60196-4.html
   My bibliography  Save this article

Restoring calcium crosstalk between ER and mitochondria promotes intestinal stem cell rejuvenation through autophagy in aged Drosophila

Author

Listed:
  • Yao Zhang

    (Tongji University)

  • Peng Ma

    (Tongji University)

  • Saifei Wang

    (Tongji University)

  • Shuxin Chen

    (Tongji University)

  • Hansong Deng

    (Tongji University)

Abstract

Breakdown of calcium network is closely associated with cellular aging. Previously, we found that cytosolic calcium (CytoCa2+) levels were elevated while mitochondrial calcium (MitoCa2+) levels were decreased and associated with metabolic shift in aged intestinal stem cells (ISCs) of Drosophila. How MitoCa2+ was decoupled from the intracellular calcium network and whether the reduction of MitoCa2+ drives ISC aging, however, remains unresolved. Here, we show that genetically restoring MitoCa2+ can reverse ISC functional decline and promote intestinal homeostasis by activating autophagy in aged flies. Further studies indicate that MitoCa2+ and Mitochondria–ER contacts (MERCs) form a positive feedback loop via IP3R to regulate autophagy independent of AMPK. Breakdown of this loop is responsible for MitoCa2+ reduction and ISC dysfunction in aged flies. Our results identify a regulatory module for autophagy initiation involving calcium crosstalk between the ER and mitochondria, providing a strategy to treat aging and age-related diseases.

Suggested Citation

  • Yao Zhang & Peng Ma & Saifei Wang & Shuxin Chen & Hansong Deng, 2025. "Restoring calcium crosstalk between ER and mitochondria promotes intestinal stem cell rejuvenation through autophagy in aged Drosophila," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60196-4
    DOI: 10.1038/s41467-025-60196-4
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-60196-4
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-60196-4?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Craig A. Micchelli & Norbert Perrimon, 2006. "Evidence that stem cells reside in the adult Drosophila midgut epithelium," Nature, Nature, vol. 439(7075), pages 475-479, January.
    2. Li He & Guangwei Si & Jiuhong Huang & Aravinthan D. T. Samuel & Norbert Perrimon, 2018. "Mechanical regulation of stem-cell differentiation by the stretch-activated Piezo channel," Nature, Nature, vol. 555(7694), pages 103-106, March.
    3. Minrui Fan & Jinru Zhang & Chen-Wei Tsai & Benjamin J. Orlando & Madison Rodriguez & Yan Xu & Maofu Liao & Ming-Feng Tsai & Liang Feng, 2020. "Structure and mechanism of the mitochondrial Ca2+ uniporter holocomplex," Nature, Nature, vol. 582(7810), pages 129-133, June.
    4. Laura García-Prat & Marta Martínez-Vicente & Eusebio Perdiguero & Laura Ortet & Javier Rodríguez-Ubreva & Elena Rebollo & Vanessa Ruiz-Bonilla & Susana Gutarra & Esteban Ballestar & Antonio L. Serrano, 2016. "Autophagy maintains stemness by preventing senescence," Nature, Nature, vol. 534(7607), pages 3-4, June.
    5. Jiajie Diao & Rong Liu & Yueguang Rong & Minglei Zhao & Jing Zhang & Ying Lai & Qiangjun Zhou & Livia M. Wilz & Jianxu Li & Sandro Vivona & Richard A. Pfuetzner & Axel T. Brunger & Qing Zhong, 2015. "ATG14 promotes membrane tethering and fusion of autophagosomes to endolysosomes," Nature, Nature, vol. 520(7548), pages 563-566, April.
    6. Benjamin Ohlstein & Allan Spradling, 2006. "The adult Drosophila posterior midgut is maintained by pluripotent stem cells," Nature, Nature, vol. 439(7075), pages 470-474, January.
    7. Saara Hämälistö & Jonathan Lucien Stahl & Elena Favaro & Qing Yang & Bin Liu & Line Christoffersen & Ben Loos & Claudia Guasch Boldú & Johanna A. Joyce & Thomas Reinheckel & Marin Barisic & Marja Jäät, 2020. "Spatially and temporally defined lysosomal leakage facilitates mitotic chromosome segregation," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    8. Shree Ram Singh & Xiankun Zeng & Jiangsha Zhao & Ying Liu & Gerald Hou & Hanhan Liu & Steven X. Hou, 2016. "The lipolysis pathway sustains normal and transformed stem cells in adult Drosophila," Nature, Nature, vol. 538(7623), pages 109-113, October.
    9. Yue Li & Pengzhen Dong & Yang Yang & Tianyu Guo & Quanyi Zhao & Dan Miao & Huanle Li & Tianfeng Lu & Fanning Xia & Jialan Lyu & Jun Ma & Thomas B. Kornberg & Qiang Zhang & Hai Huang, 2022. "Metabolic control of progenitor cell propagation during Drosophila tracheal remodeling," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    10. Maho Hamasaki & Nobumichi Furuta & Atsushi Matsuda & Akiko Nezu & Akitsugu Yamamoto & Naonobu Fujita & Hiroko Oomori & Takeshi Noda & Tokuko Haraguchi & Yasushi Hiraoka & Atsuo Amano & Tamotsu Yoshimo, 2013. "Autophagosomes form at ER–mitochondria contact sites," Nature, Nature, vol. 495(7441), pages 389-393, March.
    11. Laura García-Prat & Marta Martínez-Vicente & Eusebio Perdiguero & Laura Ortet & Javier Rodríguez-Ubreva & Elena Rebollo & Vanessa Ruiz-Bonilla & Susana Gutarra & Esteban Ballestar & Antonio L. Serrano, 2016. "Autophagy maintains stemness by preventing senescence," Nature, Nature, vol. 529(7584), pages 37-42, January.
    12. Hansong Deng & Akos A. Gerencser & Heinrich Jasper, 2015. "Signal integration by Ca2+ regulates intestinal stem-cell activity," Nature, Nature, vol. 528(7581), pages 212-217, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Junjun Gao & Song Zhang & Pan Deng & Zhigang Wu & Bruno Lemaitre & Zongzhao Zhai & Zheng Guo, 2024. "Dietary L-Glu sensing by enteroendocrine cells adjusts food intake via modulating gut PYY/NPF secretion," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    2. Kathyani Parasram & Amy Zuccato & Minjeong Shin & Reegan Willms & Brian DeVeale & Edan Foley & Phillip Karpowicz, 2024. "The emergence of circadian timekeeping in the intestine," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    3. Yue Li & Tianfeng Lu & Pengzhen Dong & Jian Chen & Qiang Zhao & Yuying Wang & Tianheng Xiao & Honggang Wu & Quanyi Zhao & Hai Huang, 2024. "A single-cell atlas of Drosophila trachea reveals glycosylation-mediated Notch signaling in cell fate specification," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    4. Seungjae Lee & Yen-Chung Chen & Austin E. Gillen & J. Matthew Taliaferro & Bart Deplancke & Hongjie Li & Eric C. Lai, 2022. "Diverse cell-specific patterns of alternative polyadenylation in Drosophila," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    5. Xingting Guo & Yongchao Zhang & Huanwei Huang & Rongwen Xi, 2022. "A hierarchical transcription factor cascade regulates enteroendocrine cell diversity and plasticity in Drosophila," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    6. Christian F. Christensen & Quentin Laurichesse & Rihab Loudhaief & Julien Colombani & Ditte S. Andersen, 2024. "Drosophila activins adapt gut size to food intake and promote regenerative growth," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    7. Daniel Jun-Kit Hu & Jina Yun & Justin Elstrott & Heinrich Jasper, 2021. "Non-canonical Wnt signaling promotes directed migration of intestinal stem cells to sites of injury," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    8. Xingting Guo & Chenhui Wang & Yongchao Zhang & Ruxue Wei & Rongwen Xi, 2024. "Cell-fate conversion of intestinal cells in adult Drosophila midgut by depleting a single transcription factor," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    9. Zoe Veneti & Virginia Fasoulaki & Nikolaos Kalavros & Ioannis S. Vlachos & Christos Delidakis & Aristides G. Eliopoulos, 2024. "Polycomb-mediated silencing of miR-8 is required for maintenance of intestinal stemness in Drosophila melanogaster," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    10. Hong Huang & Qinqin Ouyang & Min Zhu & Haijia Yu & Kunrong Mei & Rong Liu, 2021. "mTOR-mediated phosphorylation of VAMP8 and SCFD1 regulates autophagosome maturation," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    11. Elodie Mailler & Carlos M. Guardia & Xiaofei Bai & Michal Jarnik & Chad D. Williamson & Yan Li & Nunziata Maio & Andy Golden & Juan S. Bonifacino, 2021. "The autophagy protein ATG9A enables lipid mobilization from lipid droplets," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
    12. Foozhan Tahmasebinia & Yinglu Tang & Rushi Tang & Yi Zhang & Will Bonderer & Maisa Oliveira & Bretton Laboret & Songjie Chen & Ruiqi Jian & Lihua Jiang & Michael Snyder & Chun-Hong Chen & Yawei Shen &, 2025. "The 40S ribosomal subunit recycling complex modulates mitochondrial dynamics and endoplasmic reticulum - mitochondria tethering at mitochondrial fission/fusion hotspots," Nature Communications, Nature, vol. 16(1), pages 1-24, December.
    13. Marika K. Kucińska & Juliette Fedry & Carmela Galli & Diego Morone & Andrea Raimondi & Tatiana Soldà & Friedrich Förster & Maurizio Molinari, 2023. "TMX4-driven LINC complex disassembly and asymmetric autophagy of the nuclear envelope upon acute ER stress," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    14. Lifan Chen & Zisheng Fan & Jie Chang & Ruirui Yang & Hui Hou & Hao Guo & Yinghui Zhang & Tianbiao Yang & Chenmao Zhou & Qibang Sui & Zhengyang Chen & Chen Zheng & Xinyue Hao & Keke Zhang & Rongrong Cu, 2023. "Sequence-based drug design as a concept in computational drug design," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    15. Ji-Man Park & Da-Hye Lee & Do-Hyung Kim, 2023. "Redefining the role of AMPK in autophagy and the energy stress response," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    16. Agnes Banreti & Shayon Bhattacharya & Frank Wien & Koichi Matsuo & Matthieu Réfrégiers & Cornelia Meinert & Uwe Meierhenrich & Bruno Hudry & Damien Thompson & Stéphane Noselli, 2022. "Biological effects of the loss of homochirality in a multicellular organism," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    17. Koki Nakamura & Saeko Aoyama-Ishiwatari & Takahiro Nagao & Mohammadreza Paaran & Christopher J. Obara & Yui Sakurai-Saito & Jake Johnston & Yudan Du & Shogo Suga & Masafumi Tsuboi & Makoto Nakakido & , 2025. "Mitochondrial complexity is regulated at ER-mitochondria contact sites via PDZD8-FKBP8 tethering," Nature Communications, Nature, vol. 16(1), pages 1-23, December.
    18. Jiae Lee & Alejandra J. H. Cabrera & Cecilia M. T. Nguyen & Young V. Kwon, 2020. "Dissemination of RasV12-transformed cells requires the mechanosensitive channel Piezo," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    19. Zhen Yuan & Kun Cai & Jiajia Li & Ruifeng Chen & Fuhai Zhang & Xuan Tan & Yaming Jiu & Haishuang Chang & Bing Hu & Weiyi Zhang & Binbin Ding, 2024. "ATG14 targets lipid droplets and acts as an autophagic receptor for syntaxin18-regulated lipid droplet turnover," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    20. Chengyang Li & Patrick Duckney & Tong Zhang & Yanshu Fu & Xin Li & Johan Kroon & Geert Jaeger & Yunjiang Cheng & Patrick J. Hussey & Pengwei Wang, 2022. "TraB family proteins are components of ER-mitochondrial contact sites and regulate ER-mitochondrial interactions and mitophagy," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60196-4. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.