Hypoxia induced mitophagy generates reversible metabolic and redox heterogeneity with transient cell death switch driving tumorigenesis

Abstract

Tumor hypoxia determines tumor growth, metastasis, drug resistance, and tumor heterogeneity through multiple mechanisms, largely dependent on the extent of hypoxia, further modulated by re-oxygenation events. In order to track the cell fates under hypoxia and re-oxygenation, we have developed a sensor cell for real-time tracking of apoptotic, necrotic, and surviving mitophagy cells under hypoxia and re-oxygenation. The study using this sensor revealed a cell death switch from apoptosis to necrosis by hypoxia-exposed cells under re-oxygenation, where mitophagy plays a key role in acquiring temporally evolving functional phenotypes, including metabolic heterogeneity and mitochondrial redox heterogeneity. RNA transcriptomics also revealed a temporally evolving genomic landscape supporting the complex transcriptional plasticity of cells as a non-genetic adaptive event. Interestingly, cells regained from these distinct stages retained their metastatic potential despite slow growth in animal models. Overall, the study demonstrated that cells acquire distinct functions by tumor hypoxia and re-oxygenation, secondarily acquiring transient functional traits and metabolic heterogeneity governed by cell inherent mitochondrial dynamics. Such cell autonomous temporal alterations in cell states governed by organelle integrity with distinct cell proliferation and apoptosis-necrosis switch may be advantageous for the growing tumor to evolve under complex microenvironmental stress, further contributing to tumorigenesis.