Spatial patterns of hepatocyte glucose flux revealed by stable isotope tracing and multi-scale microscopy.

Journal: Nature communications
Published Date: Jul 1, 2025

Abstract

Metabolic homeostasis requires engagement of catabolic and anabolic pathways consuming nutrients that generate and consume energy and biomass. Our current understanding of cell homeostasis and metabolism, including how cells utilize nutrients, comes largely from tissue and cell models analyzed after fractionation, and that fail to reveal the spatial characteristics of cell metabolism, and how these aspects relate to the location of cells and organelles within tissue microenvironments. Here we show the application of multi-scale microscopy, machine learning-based image segmentation, and spatial analysis tools to quantitatively map the fate of nutrient-derived C atoms across spatiotemporal scales. This approach reveals the cellular and organellar features underlying the spatial pattern of glucose C flux in hepatocytes in situ, including the timeline of mitochondria-ER contact dynamics in response to changes in blood glucose levels, and the discovery of the ultrastructural relationship between glycogenesis and lipid droplets.

Authors

  • Aliyah Habashy
    Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA.
  • Christopher Acree
    Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA.
  • Keun-Young Kim
    National Center for Microscopy and Imaging Research, Department of Neurosciences, University of California San Diego, La Jolla, CA 92039, USA.
  • Ali Zahraei
    Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA.
  • Martin Dufresne
    Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA.
  • Sébastien Phan
    National Center for Microscopy and Imaging Research, Department of Neurosciences, University of California San Diego, La Jolla, CA 92039, USA.
  • Melanie Cutler
    Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA.
  • Emilee Patterson
    Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA.
  • Alexandra G Mulligan
    Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA.
  • Kristopher Burkewitz
    Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA.
  • Charles Robert Flynn
    Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.
  • Louise Lantier
    Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA.
  • Thomas Deerinck
    National Center for Imaging and Microscopy Research (NCMIR) and the Department of Neurosciences, University of California San Diego, School of Medicine, La Jolla, CA, USA.
  • Owen P McGuinness
    Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA.
  • Jeffrey M Spraggins
    Mass Spectrometry Research Center, Vanderbilt University, Nashville, TN, USA; Department of Biochemistry, Vanderbilt University, Nashville, TN, USA; Department of Chemistry, Vanderbilt University, Nashville, TN, USA.
  • Mark H Ellisman
    National Center for Microscopy and Imaging Research, Department of Neurosciences, University of California San Diego, La Jolla, CA 92039, USA.
  • Rafael Arrojo E Drigo
    Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA. r.drigo@vanderbilt.edu.

Keywords

External Resources

Popular Topics
Recent Journals