TY - JOUR T1 - Fine-tuned repression of Drp1 driven mitochondrial fission primes a ‘stem/progenitor-like state’ to accelerate neoplastic transformation JF - bioRxiv DO - 10.1101/2021.03.05.434102 SP - 2021.03.05.434102 AU - B Spurlock AU - D Parker AU - MK Basu AU - A Hjelmeland AU - G Sajina AU - S Liu AU - GP Siegal AU - A Gunter AU - A Moran AU - K Mitra Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/03/24/2021.03.05.434102.abstract N2 - The opposing processes of mitochondrial fission and fusion are emerging as crucial regulators of stemness. Gene knockout of the master regulator of mitochondrial fission, Drp1, prevents neoplastic transformation. However, stem/progenitor cells maintaining repressed mitochondrial fission are primed for self-renewal and proliferation. Here, we demonstrate that only fine-tuned repression of Drp1 establishes a ‘stem/progenitor-like state’ towards supporting carcinogen driven neoplastic transformation of keratinocytes, while more complete Drp1 repression prevents it. Only fine-tuned Drp1 repression maintains small networks of fused mitochondria to sustain a unique gene-expression profile with elevated stem/progenitor cell functional markers (Krt15, Sox2 etc) and their regulators (Cyclin E). Cells with such a mitochondria-primed state are slow cycling, susceptible to transformation, and when enriched by mild carcinogen exposure sustains elevated self-renewal/proliferation to form less differentiated tumors. Therefore, our data for the first time highlights a ‘goldilocks’ level of Drp1 repression that supports stem/progenitor state dependent neoplastic transformation.Competing Interest StatementThe authors have declared no competing interest. ER -