Esophageal squamous cell carcinoma (ESCC) is an aggressive
cancer with late-stage detection and poor prognosis. This emphasizes the need to identify new markers for early diagnosis and treatment. Altered mitochondrial genome (
mtDNA) content in primary
tumors correlates with poor patient prognosis. Here we used three-dimensional (3D) organoids of esophageal epithelial cells (EECs) from the MPV17-/- mouse model of
mtDNA depletion to investigate the contribution of reduced
mtDNA content in ESCC oncogenicity. To test if
mtDNA defects are a contributing factor in ESCC, we used oncogenic stimuli such as ESCC
carcinogen 4-nitroquinoline
oxide (4-NQO) treatment, or expressing p53R175H oncogenic driver mutation. We observed that EECs and 3D-organoids with
mtDNA depletion had cellular, morphological and genetic alterations typical of an oncogenic transition. Furthermore,
mitochondrial dysfunction induced cellular transformation is accompanied by elevated mitochondrial fission
protein, DRP1 and pharmacologic inhibition of mitochondrial fission by
mDivi-1 in the MPV17-/- organoids reversed the phenotype to that of normal EEC organoids. Our studies show that
mtDNA copy number depletion, activates a mitochondrial retrograde response, potentiates telomere defects, and increases the oncogenic susceptibility towards ESCC. Furthermore,
mtDNA depletion driven cellular plasticity is mediated via altered mitochondrial fission-fusion dynamics.