Hypoxia signaling pathways: modulators of oxygen-related organelles

Oxygen (O-2) is an essential substrate in cellular metabolism, bioenergetics, and signaling and as such linked to the survival and normal function of all metazoans. Low O-2 tension (hypoxia) is a fundamental feature of physiological processes as well as pathophysiological conditions such as cancer and ischemic diseases. Central to the molecular mechanisms underlying O-2 homeostasis are the hypoxia-inducible factors-1 and -2 alpha (HIF-1 alpha and EPAS1/HIF-2 alpha) that function as master regulators of the adaptive response to hypoxia. HIF-induced genes promote characteristic tumor behaviors, including angiogenesis and metabolic reprogramming. The aim of this review is to critically explore current knowledge of how HIF-alpha signaling regulates the abundance and function of major O-2-consuming organelles. Abundant evidence suggests key roles for HIF-1 alpha in the regulation of mitochondrial homeostasis. An essential adaptation to sustained hypoxia is repression of mitochondrial respiration and induction of glycolysis. HIF-1 alpha activates several genes that trigger mitophagy and represses regulators of mitochondrial biogenesis. Several lines of evidence point to a strong relationship between hypoxia, the accumulation of misfolded proteins in the endoplasmic reticulum, and activation of the unfolded protein response. Surprisingly, although peroxisomes depend highly on molecular O-2 for their function, there has been no evidence linking HIF signaling to peroxisomes. We discuss our recent findings that establish HIF-2 alpha as a negative regulator of peroxisome abundance and suggest a mechanism by which cells attune peroxisomal function with O-2 availability. HIF-2 alpha activation augments peroxisome turnover by pexophagy and thereby changes lipid composition reminiscent of peroxisomal disorders. We discuss potential mechanisms by which HIF-2 alpha might trigger pexophagy and place special emphasis on the potential pathological implications of HIF-2 alpha-mediated pexophagy for human health.