Cellular adaptation to hypoxia through hypoxia inducible factors and beyond

Abstract

Molecular oxygen (O 2 ) sustains intracellular bioenergetics and is consumed by numerous biochemical reactions, making it essential for most species on Earth. Accordingly, decreased O 2 concentrations (hypoxia) is a major stressor that generally subverts life of aerobic species and is a prominent feature of pathological states encountered in bacterial infection, inflammation, wounds, cardiovascular defects, and cancer. Therefore, key adaptive mechanisms to cope with hypoxia have evolved in mammals. Systemically, these adaptations include increased ventilation, cardiac output, blood vessel growth, and circulating red blood cell numbers. On a cellular level, ATP consuming reactions are suppressed and metabolism is altered until oxygen homeostasis is restored. A critical question is how mammalian cells sense O 2 levels to coordinate diverse biological outputs during hypoxia. The best studied mechanism of response to hypoxia involves hypoxia inducible factors (HIFs), which are stabilized by low oxygen availability and control the expression of a multitude of genes, including those involved in cell survival, angiogenesis, glycolysis, and invasion/metastasis. Importantly, changes in O 2 can also be sensed via other stress pathways as well as changes in metabolite levels and the generation of reactive oxygen species (ROS) by mitochondria. Collectively, this leads to cellular adaptations of protein synthesis, energy metabolism, mitochondrial respiration, lipid and carbon metabolism as well as nutrient acquisition. These mechanisms are integral inputs into fine tuning the responses to hypoxic stress. The transcriptional response to hypoxia and the role of hypoxia inducible factors have been extensively studied. Yet, hypoxic cells also adapt to hypoxia by modulating protein synthesis, metabolism and nutrient uptake. Understanding these processes could shed light on pathologies associated with hypoxia, including cardiovascular diseases and cancer, and disease mechanisms such as inflammation and wound repair.