Mitochondria and Hypoxia: Metabolic Crosstalk in Cell-Fate Decisions

Alignment of transcriptional activity with nutrient availability is crucial to maintain homeostasis in mammalian cells. The 2-oxoglutarate-dependent dioxygenase (2OGDD) superfamily integrates mitochondrial metabolic signals to coordinate downstream transcriptional responses. Oxygen and mitochondrial metabolite concentrations signal via 2OGDDs to alter DNA/histone methylation and hypoxic transcriptional activity. Targeting 2OGDD activity affects cell fate in vivo and has relevance in the treatment of immune diseases and cancer. Alterations in mitochondrial metabolism influence cell differentiation and growth. This process is regulated by the activity of 2-oxoglutarate (2OG)-dependent dioxygenases (2OGDDs) – a diverse superfamily of oxygen-consuming enzymes – through modulation of the epigenetic landscape and transcriptional responses. Recent reports have described the role of mitochondrial metabolites in directing 2OGDD-driven cell-fate switches in stem cells (SCs), immune cells, and cancer cells. An understanding of the metabolic mechanisms underlying 2OGDD autoregulation is required for therapeutic targeting of this system. We propose a model dependent on oxygen and metabolite availability and discuss how this integrates 2OGDD metabolic signalling, the hypoxic transcriptional response, and fate-determining epigenetic changes. Alterations in mitochondrial metabolism influence cell differentiation and growth. This process is regulated by the activity of 2-oxoglutarate (2OG)-dependent dioxygenases (2OGDDs) – a diverse superfamily of oxygen-consuming enzymes – through modulation of the epigenetic landscape and transcriptional responses. Recent reports have described the role of mitochondrial metabolites in directing 2OGDD-driven cell-fate switches in stem cells (SCs), immune cells, and cancer cells. An understanding of the metabolic mechanisms underlying 2OGDD autoregulation is required for therapeutic targeting of this system. We propose a model dependent on oxygen and metabolite availability and discuss how this integrates 2OGDD metabolic signalling, the hypoxic transcriptional response, and fate-determining epigenetic changes.