Fine-tuned repression of Drp1 driven mitochondrial fission primes a 'stem/progenitor-like state' to support neoplastic transformation

Abstract

Gene knockout of the master regulator of mitochondrial fission, Drp1, prevents neoplastic transformation. Also, mitochondrial fission and its opposing process of mitochondrial fusion are emerging as crucial regulators of stemness. Intriguingly, stem/progenitor cells maintaining repressed mitochondrial fission are primed for self-renewal and proliferation. Using our newly derived carcinogen transformed human cell model we demonstrate that fine-tuned Drp1 repression primes a slow cycling 'stem/progenitor-like state', which is characterized by small networks of fused mitochondria and a gene-expression profile with elevated functional stem/progenitor markers (Krt15, Sox2 etc) and their regulators (Cyclin E). Fine tuning Drp1 protein by reducing its activating phosphorylation sustains the neoplastic stem cell markers. Whereas, fine-tuned reduction of Drp1 protein maintains the characteristic mitochondrial shape and gene-expression of the primed 'stem/progenitor-like state' to accelerate neoplastic transformation, and more complete reduction of Drp1 protein prevents it. Therefore, our data highlights a 'goldilocks'; level of Drp1 repression supporting stem/progenitor state dependent neoplastic transformation.

Data availability

Details pertaining to the sc-RNAseq experiment are available as Supplementary data Tables 1, 2, 3. Raw, analyzed and meta data are available in Gene expression omnibus (GEO GSE171772).

The following data sets were generated

Article and author information

Author details

  1. Brian Spurlock

    Genetics, University of Alabama at Birmingham, Birmingham, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9757-4494
  2. Danitra Parker

    Genetics, University of Alabama at Birmingham, Birmingham, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Malay Kumar Basu

    Pathology, University of Alabama at Birmingham, Birmingham, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Anita Hjelmeland

    Pathology, University of Alabama at Birmingham, Birmingham, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Sajina GC

    Cell Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2676-2794
  6. Shanrun Liu

    Medicine, University of Alabama at Birmingham, Birmingham, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Gene P Siegal

    Pathology, University of Alabama at Birmingham, Birmingham, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Alan Gunter

    Genetics, University of Alabama at Birmingham, Birmingham, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Aida Moran

    Genetics, University of Alabama at Birmingham, Birmingham, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Kasturi Mitra

    Genetics, University of Alabama at Birmingham, Birmingham, United States
    For correspondence
    kasturi@uab.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3718-7094

Funding

National Institute of Environmental Health Sciences (R33ES025662)

  • Kasturi Mitra

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

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 (IACUC-21347) of the University of Alabama at Birmingham. All mice were be examined daily, and were euthanized by CO2 inhalation, and death confirmed by cervical dislocation, as approved by the IACUC protocol.

Reviewing Editor

  1. Utpal Banerjee, University of California, Los Angeles, United States

Publication history

  1. Preprint posted: March 5, 2021 (view preprint)
  2. Received: March 15, 2021
  3. Accepted: September 8, 2021
  4. Accepted Manuscript published: September 21, 2021 (version 1)
  5. Version of Record published: October 7, 2021 (version 2)

Copyright

© 2021, Spurlock 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. Brian Spurlock
  2. Danitra Parker
  3. Malay Kumar Basu
  4. Anita Hjelmeland
  5. Sajina GC
  6. Shanrun Liu
  7. Gene P Siegal
  8. Alan Gunter
  9. Aida Moran
  10. Kasturi Mitra
(2021)
Fine-tuned repression of Drp1 driven mitochondrial fission primes a 'stem/progenitor-like state' to support neoplastic transformation
eLife 10:e68394.
https://doi.org/10.7554/eLife.68394

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    This study’s literature retrieval was supported financially by the 345 Talent Project of Shengjing Hospital of China Medical University (M0949 to Tao Zhang).