Fine-tuned repression of Drp1 driven mitochondrial fission primes a 'stem/progenitor-like state' to support neoplastic transformation
- University of Alabama at Birmingham, United States
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).
Article and author information
Author details
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.
Reviewing Editor
- Utpal Banerjee, University of California, Los Angeles, 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 (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.
Version history
- Preprint posted: March 5, 2021 (view preprint)
- Received: March 15, 2021
- Accepted: September 8, 2021
- Accepted Manuscript published: September 21, 2021 (version 1)
- 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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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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