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

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 mitochondri...

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Autores principales:	Brian Spurlock, Danitra Parker, Malay Kumar Basu, Anita Hjelmeland, Sajina GC, Shanrun Liu, Gene P Siegal, Alan Gunter, Aida Moran, Kasturi Mitra
Formato:	article
Lenguaje:	EN
Publicado:	eLife Sciences Publications Ltd 2021
Materias:	mitochondrial fission Drp1 stem/progenitor state keratinocytes neoplastic transformation single cell confocal microscopy Medicine R Science Q Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/2ab7693ce4904efebfa69daa7782a588
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spelling	oai:doaj.org-article:2ab7693ce4904efebfa69daa7782a5882021-11-25T10:26:46ZFine-tuned repression of Drp1-driven mitochondrial fission primes a ‘stem/progenitor-like state’ to support neoplastic transformation10.7554/eLife.683942050-084Xe68394https://doaj.org/article/2ab7693ce4904efebfa69daa7782a5882021-09-01T00:00:00Zhttps://elifesciences.org/articles/68394https://doaj.org/toc/2050-084XGene 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.Brian SpurlockDanitra ParkerMalay Kumar BasuAnita HjelmelandSajina GCShanrun LiuGene P SiegalAlan GunterAida MoranKasturi MitraeLife Sciences Publications Ltdarticlemitochondrial fissionDrp1stem/progenitor statekeratinocytesneoplastic transformationsingle cell confocal microscopyMedicineRScienceQBiology (General)QH301-705.5ENeLife, Vol 10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	mitochondrial fission Drp1 stem/progenitor state keratinocytes neoplastic transformation single cell confocal microscopy Medicine R Science Q Biology (General) QH301-705.5
spellingShingle	mitochondrial fission Drp1 stem/progenitor state keratinocytes neoplastic transformation single cell confocal microscopy Medicine R Science Q Biology (General) QH301-705.5 Brian Spurlock Danitra Parker Malay Kumar Basu Anita Hjelmeland Sajina GC Shanrun Liu Gene P Siegal Alan Gunter Aida Moran Kasturi Mitra Fine-tuned repression of Drp1-driven mitochondrial fission primes a ‘stem/progenitor-like state’ to support neoplastic transformation
description	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.
format	article
author	Brian Spurlock Danitra Parker Malay Kumar Basu Anita Hjelmeland Sajina GC Shanrun Liu Gene P Siegal Alan Gunter Aida Moran Kasturi Mitra
author_facet	Brian Spurlock Danitra Parker Malay Kumar Basu Anita Hjelmeland Sajina GC Shanrun Liu Gene P Siegal Alan Gunter Aida Moran Kasturi Mitra
author_sort	Brian Spurlock
title	Fine-tuned repression of Drp1-driven mitochondrial fission primes a ‘stem/progenitor-like state’ to support neoplastic transformation
title_short	Fine-tuned repression of Drp1-driven mitochondrial fission primes a ‘stem/progenitor-like state’ to support neoplastic transformation
title_full	Fine-tuned repression of Drp1-driven mitochondrial fission primes a ‘stem/progenitor-like state’ to support neoplastic transformation
title_fullStr	Fine-tuned repression of Drp1-driven mitochondrial fission primes a ‘stem/progenitor-like state’ to support neoplastic transformation
title_full_unstemmed	Fine-tuned repression of Drp1-driven mitochondrial fission primes a ‘stem/progenitor-like state’ to support neoplastic transformation
title_sort	fine-tuned repression of drp1-driven mitochondrial fission primes a ‘stem/progenitor-like state’ to support neoplastic transformation
publisher	eLife Sciences Publications Ltd
publishDate	2021
url	https://doaj.org/article/2ab7693ce4904efebfa69daa7782a588
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Fine-tuned repression of Drp1-driven mitochondrial fission primes a ‘stem/progenitor-like state’ to support neoplastic transformation

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