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Spatial mapping of hepatic ER and mitochondria architecture reveals zonated remodeling in fasting and obesity

Author

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  • Güneş Parlakgül

    (Harvard T.H. Chan School of Public Health
    University of California, Berkeley)

  • Song Pang

    (HHMI Janelia Research Campus
    Yale School of Medicine)

  • Leonardo L. Artico

    (University of California, Berkeley)

  • Nina Min

    (Harvard T.H. Chan School of Public Health)

  • Erika Cagampan

    (Harvard T.H. Chan School of Public Health)

  • Reyna Villa

    (University of California, Berkeley)

  • Renata L. S. Goncalves

    (Harvard T.H. Chan School of Public Health)

  • Grace Yankun Lee

    (Harvard T.H. Chan School of Public Health)

  • C. Shan Xu

    (HHMI Janelia Research Campus
    Yale School of Medicine)

  • Gökhan S. Hotamışlıgil

    (Harvard T.H. Chan School of Public Health
    Broad Institute of MIT and Harvard)

  • Ana Paula Arruda

    (University of California, Berkeley
    Chan Zuckerberg Biohub)

Abstract

The hepatocytes within the liver present an immense capacity to adapt to changes in nutrient availability. Here, by using high resolution volume electron microscopy, we map how hepatic subcellular spatial organization is regulated during nutritional fluctuations and as a function of liver zonation. We identify that fasting leads to remodeling of endoplasmic reticulum (ER) architecture in hepatocytes, characterized by the induction of single rough ER sheet around the mitochondria, which becomes larger and flatter. These alterations are enriched in periportal and mid-lobular hepatocytes but not in pericentral hepatocytes. Gain- and loss-of-function in vivo models demonstrate that the Ribosome receptor binding protein1 (RRBP1) is required to enable fasting-induced ER sheet-mitochondria interactions and to regulate hepatic fatty acid oxidation. Endogenous RRBP1 is enriched around periportal and mid-lobular regions of the liver. In obesity, ER-mitochondria interactions are distinct and fasting fails to induce rough ER sheet-mitochondrion interactions. These findings illustrate the importance of a regulated molecular architecture for hepatocyte metabolic flexibility.

Suggested Citation

  • Güneş Parlakgül & Song Pang & Leonardo L. Artico & Nina Min & Erika Cagampan & Reyna Villa & Renata L. S. Goncalves & Grace Yankun Lee & C. Shan Xu & Gökhan S. Hotamışlıgil & Ana Paula Arruda, 2024. "Spatial mapping of hepatic ER and mitochondria architecture reveals zonated remodeling in fasting and obesity," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48272-7
    DOI: 10.1038/s41467-024-48272-7
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    References listed on IDEAS

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