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

Elife. 2021 Sep 21:10:e68394. doi: 10.7554/eLife.68394.


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/progenitor 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.

Keywords: Drp1; cancer biology; cell biology; keratinocytes; mitochondrial fission; mouse; neoplastic transformation; single cell confocal microscopy; single cell transcriptomics; stem/progenitor state.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Proliferation
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism*
  • Cyclin E / genetics
  • Cyclin E / metabolism
  • Dynamins / genetics
  • Dynamins / metabolism*
  • HaCaT Cells
  • Humans
  • Keratin-15 / genetics
  • Keratin-15 / metabolism
  • Keratinocytes / cytology
  • Keratinocytes / metabolism
  • Mitochondrial Dynamics*
  • Phosphorylation
  • SOXB1 Transcription Factors / genetics
  • SOXB1 Transcription Factors / metabolism
  • Stem Cells / metabolism*


  • Cyclin E
  • KRT15 protein, human
  • Keratin-15
  • SOX2 protein, human
  • SOXB1 Transcription Factors
  • DNM1L protein, human
  • Dynamins

Associated data

  • GEO/GSE171772