Regulation of Epithelial Autophagy by Hypoxia-Inducible Factor

(Macro)autophagy is a highly conserved eukaryotic system in which cytosolic constituents are targeted to the lysosome for degradation and recycling. It is essential for normal cellular homeostasis and maintenance of tissue function, and defects in autophagy have been associated with the pathogenesis of numerous diseases. Among these, inflammatory bowel disease (IBD) has been associated at a genetic level with defects in intestinal epithelial autophagy. Therapies that potentiate autophagy have shown promise in the treatment of IBD in animal models and in isolated case reports; thus, autophagy as a pathway may be a logical target for future drug intervention. However, current approaches are constrained by our incomplete understanding of the regulation of autophagy in the epithelium. A more complete understanding of the mechanism(s) controlling autophagy would provide a logical starting point for the development of novel IBD treatments. One major pathway regulating autophagy in the intestinal epithelium is signaling mediated by the transcription factor family hypoxia-inducible factor (HIF). This family, which is composed of oxygen-labile alpha subunits and a constitutively present beta subunit, guides the cellular response to numerous stressors including hypoxia, oxidative stress, and iron depletion. Past work from our group and others has implicated activation of HIF with increased autophagic flux. However, the specific form of autophagy, as well as the HIF-alpha paralog responsible for this increase, is unclear. In this work, we leverage recently developed technologies to demonstrate that activation of HIF induces LC3-dependent (selective) autophagy and, notably, results in a “shunt” of autophagic machinery away from nonselective (bulk) autophagy. Further, we show that this shift is specifically dependent on HIF-1a, with HIF-2a having little role in the acute induction of autophagy resulting from HIF stabilization. We further demonstrate a potent targeting of mitochondria (mitophagy) resulting from HIF-1a-dependent activation of selective autophagy. These results, taken together, validate previous findings using modern techniques and establish HIF activation as a potential avenue for treatment of various disorders including IBD. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.