The regulation of hypoxia tolerance

Our cells and organs need oxygen from the air we breathe in order to survive and function. However, in certain disorders such as stroke, heart disease and cancer, tissues are often deprived of oxygen. This lack of oxygen, known as hypoxia, leads to the tissue damage and deregulation that are characteristic of these diseases. Understanding how tissues and organs respond to low oxygen is therefore an important question in biomedical research.

Using Drosophila as an in vivo model system, we discovered that the fly adipose tissue (the fat body) functions as a key hypoxic sensor that controls whole body hypoxia tolerance (Lee et al, 2019) . Specifically, we identified hypoxia suppression of the conserved Target-Of-Rapamycin (TOR) kinase signaling pathway as the trigger for this hypoxia response. Inhibition of TOR was required to remodel fat body lipid metabolism, which, in turn, promoted a non-autonomous, whole-body protection against the lethal effects of hypoxia.

We also showed that the FOXO transcription factor is required hypoxia tolerance, in part due to its ability to induce immune-like responses via the immune transcription factor Relish/NF-KappaB (Barretto et al 2020).

We are currently addressing several questions raised by our work:

  • How does hypoxia control TOR and immune signaling?
  • How do changes in cell and tissue metabolism contribute to hypoxia tolerance?
  • Do tissue-specific effects of TOR or immune signaling contribute to whole-body hypoxia tolerance?