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Cited by 81Advanced Electron Microscopy Techniques and ApplicationsMitochondrial Function and PathologyCell Image Analysis Techniques

Quantifying organellar ultrastructure in cryo-electron tomography using a surface morphometrics pipeline

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Barad, Benjamin A., Medina, Michaela, Fuentes, Daniel, Wiseman, R. Luke, Grotjahn, Danielle A.·2023·Journal of Cell Biology
DOI 10.1083/jcb.202204093PMC PMC9960335

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Abstract

Cellular cryo-electron tomography (cryo-ET) enables three-dimensional reconstructions of organelles in their native cellular environment at subnanometer resolution. However, quantifying ultrastructural features of pleomorphic organelles in three dimensions is challenging, as is defining the significance of observed changes induced by specific cellular perturbations. To address this challenge, we established a semiautomated workflow to segment organellar membranes and reconstruct their underlying surface geometry in cryo-ET. To complement this workflow, we developed an open-source suite of ultrastructural quantifications, integrated into a single pipeline called the surface morphometrics pipeline. This pipeline enables rapid modeling of complex membrane structures and allows detailed mapping of inter- and intramembrane spacing, curvedness, and orientation onto reconstructed membrane meshes, highlighting subtle organellar features that are challenging to detect in three dimensions and allowing for statistical comparison across many organelles. To demonstrate the advantages of this approach, we combine cryo-ET with cryo-fluorescence microscopy to correlate bulk mitochondrial network morphology (i.e., elongated versus fragmented) with membrane ultrastructure of individual mitochondria in the presence and absence of endoplasmic reticulum (ER) stress. Using our pipeline, we demonstrate ER stress promotes adaptive remodeling of ultrastructural features of mitochondria including spacing between the inner and outer membranes, local curvedness of the inner membrane, and spacing between mitochondrial cristae. We show that differences in membrane ultrastructure correlate to mitochondrial network morphologies, suggesting that these two remodeling events are coupled. Our pipeline offers opportunities for quantifying changes in membrane ultrastructure on a single-cell level using cryo-ET, opening new opportunities to define changes in ultrastructural features induced by diverse types of cellular perturbations.

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  • For larger and thicker samples, cryo-FIB milling combined with CLEM has been developed to access regions deep within cells.

    “In contrast, for larger and thicker samples, cryo-focused ion beam (cryo-FIB) milling combined with correlative light and electron microscopy (CLEM) has been developed to access regions deep within cells8.”

    From Ghost Neuron preparation unlocks high-resolution structural mapping of intracellular architecture in axons (2026) · cites this paper as [8]

    The Results (Figure 1 caption; page unavailable) describe using cryo-fluorescence microscopy to select cells for cryo-FIB milling into thin lamellae, supporting the combined CLEM–cryo-FIB approach. The passages do not say that this approach was developed specifically for larger or thicker samples or to access regions deep within cells. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Barad, B. A., Medina, M., Fuentes, D., Wiseman, R. L., & Grotjahn, D. A.
Affiliations
Scripps Research Institute (US)
Corresponding author
Grotjahn, Danielle A.
ORCID
Venue
Journal of Cell Biology
Publisher
Rockefeller University Press
Published
2023-02-14
Volume
222
Issue
4
ISSN
  • 0021-9525 (ISSN-L)
  • 1540-8140
DOI
10.1083/jcb.202204093
PMC
PMC9960335
OpenAlex
W4320710123
Cited by
81
References
4
Citations by year
2026: 24 · 2025: 25 · 2024: 18 · 2023: 9 · 2022: 3 · 2021: 1 · 2012: 1
FWCI
6.65
Type
journal article
Language
en
Open access
Licence
Locations
  • The Journal of Cell Biology (publishedVersion, cc-by-nc-sa)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
Funders
  • Damon Runyon Cancer Research Foundation (DRR-65-21)
  • American Cancer Society (PF-21-075-01-CCB)
  • National Institutes of Health (RF1NS125674, R01NS095892)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Advanced Electron Microscopy Techniques and Applications
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biophysics › Cell Image Analysis Techniques
Keywords
membrane segmentation, membrane curvature, mitochondrial ultrastructure, mitochondrial network morphology, endoplasmic reticulum stress, mitochondrial cristae, inner membrane, cryo-electron tomography, organelle remodeling
MeSH terms
Mitochondria, Cryoelectron Microscopy, Mitochondrial Membranes, Electron Microscope Tomography, Endoplasmic Reticulum Stress

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