Abstract

Differentiating cells tailor their metabolism to fulfill their specialized functions. We examined whether mitochondrial fusion is important for metabolic tailoring during spermatogenesis. Acutely after depletion of mitofusins Mfn1 and Mfn2, spermatogenesis arrests due to failure to accomplish a metabolic shift during meiosis. This metabolic shift includes increased mitochondrial content, mitochondrial elongation, and upregulation of oxidative phosphorylation (OXPHOS). With long-term mitofusin loss, all differentiating germ cell types are depleted, but proliferation of stem-like undifferentiated spermatogonia remains unaffected. Thus, compared with undifferentiated spermatogonia, differentiating spermatogonia and meiotic spermatocytes have cell physiologies that require high levels of mitochondrial fusion. Proteomics in fibroblasts reveals that mitofusin-null cells downregulate respiratory chain complexes and mitochondrial ribosomal subunits. Similarly, mitofusin depletion in immortalized spermatocytes or germ cells in vivo results in reduced OXPHOS subunits and activity. We reveal that by promoting OXPHOS, mitofusins enable spermatogonial differentiation and a metabolic shift during meiosis.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Grigor Varuzhanyan

    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Rebecca Rojansky

    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Michael J Sweredoski

    Proteome Exploration Laboratory of the Beckman Institute, California Institute of Technology, Pasadena, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0878-3831
  4. Robert LJ Graham

    Proteome Exploration Laboratory of the Beckman Institute, California Institute of Technology, Pasadena, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Sonja Hess

    Proteome Exploration Laboratory of the Beckman Institute, California Institute of Technology, Pasadena, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Mark S Ladinsky

    The Beckman Resource Center for Transmission Electron Microscopy, California Institute of Technology, Pasadena, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. David C Chan

    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States
    For correspondence
    dchan@caltech.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0191-2154

Funding

National Institutes of Health (R35 GM127147)

  • David C Chan

National Institutes of Health (GM119388)

  • David C Chan

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Serge Przedborski, Columbia University Medical Center, United States

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols of the California Institute of Technology.

Version history

  1. Received: September 4, 2019
  2. Accepted: September 27, 2019
  3. Accepted Manuscript published: October 9, 2019 (version 1)
  4. Version of Record published: October 22, 2019 (version 2)
  5. Version of Record updated: July 23, 2020 (version 3)
  6. Version of Record updated: April 11, 2022 (version 4)

Copyright

© 2019, Varuzhanyan et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Grigor Varuzhanyan
  2. Rebecca Rojansky
  3. Michael J Sweredoski
  4. Robert LJ Graham
  5. Sonja Hess
  6. Mark S Ladinsky
  7. David C Chan
(2019)
Mitochondrial fusion is required for spermatogonial differentiation and meiosis
eLife 8:e51601.
https://doi.org/10.7554/eLife.51601

Share this article

https://doi.org/10.7554/eLife.51601

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