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

Autor:	Spurlock B; Department of Genetics, University of Alabama at Birmingham, Birmingham, United States., Parker D; Department of Genetics, University of Alabama at Birmingham, Birmingham, United States., Basu MK; Departments of Pathology, University of Alabama at Birmingham, Birmingham, United States., Hjelmeland A; Department of Cell Development and Integrative Biology, University of Alabama at Birmingham, Birmingham, United States., Gc S; Department of Cell Development and Integrative Biology, University of Alabama at Birmingham, Birmingham, United States., Liu S; Department of Genetics, University of Alabama at Birmingham, Birmingham, United States., Siegal GP; Departments of Pathology, Surgery, Genetics and Cell and Developmental Biology, University of Alabama at Birmingham, Birmingham, United States., Gunter A; Department of Genetics, University of Alabama at Birmingham, Birmingham, United States., Moran A; Department of Genetics, University of Alabama at Birmingham, Birmingham, United States., Mitra K; Department of Genetics, University of Alabama at Birmingham, Birmingham, United States.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2021 Sep 21; Vol. 10. Date of Electronic Publication: 2021 Sep 21.
DOI:	10.7554/eLife.68394
Abstrakt:	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. Competing Interests: BS, DP, MB, AH, SG, SL, GS, AG, AM, KM No competing interests declared (© 2021, Spurlock et al.)
Databáze:	MEDLINE
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