Fine-tuned repression of Drp1 driven mitochondrial fission primes a slow cycling stem/progenitor-like state towards accelerating neoplastic transformation of keratinocytes

The opposing processes of mitochondrial fission and fusion are emerging as crucial regulators of stem cells. Stem/progenitor cells maintaining repressed mitochondrial fission appear to be primed for self-renewal and proliferation. Here, we demonstrate the causative role of fine-tuned repression of Drp1, the master regulator of mitochondrial fission, in establishing a stem/progenitor-like state towards supporting carcinogen (TCDD) driven neoplastic transformation of keratinocytes. 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 this 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. More complete Drp1 repression sustains larger hyperfused mitochondria, represses lineage specific stem/progenitor genes and prevents transformation. Therefore, our data highlights a goldilocks level of Drp1 repression that supports stem/progenitor cell dependent neoplastic transformation. Future studies would reveal if bodily stresses causing mild Drp1 repression could enrich this mitochondria-primed stem/progenitor like population in tissues making them vulnerable to neoplastic transformation.