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  • Most studies of HIF have

    2022-01-14

    Most studies of HIF-1α have focused on its transcriptional activity-dependent functions. However, our results indicate that the oxidative stress-related effects of mtHIF-1α occur independently of its translocation to the nucleus and do not require its transcriptional activity. In fact, several studies have identified functions for HIF-1α outside the nucleus. Khan et al. found that HIF-1α co-localized with peroxisomes, not the nucleus, in primary rat hepatocytes during hypoxia–reoxygenation [33]. Hubbi et al. showed that HIF-1α inhibits DNA replication during the cell cycle by direct binding to Cdc6, which promotes Cdc6 interaction with the minichromosome maintenance complex and results in reduced replication-origin firing under hypoxia [34]. Clearly, HIF-1α functions do not always involve its transcriptional activity and may occur at various subcellular locations outside the nucleus. Intriguingly, other transcription factors have also been shown to translocate to the mitochondria; some of these affect mitochondrial gene expression while others interact with regulatory molecules. Ogita et al. revealed that the activator protein-1 (AP-1) complex binds to AP-1-like sites in non-coding regions of the mitochondrial genome [35], [36]. Other studies showed that NF-κB can move to the mitochondrial intermembrane space, where it negatively regulates mitochondrial mRNA expression [37], [38], [39]. CREB and p53 also relocate to the mitochondria. CREB binds to its cognate responsive elements in the D-loop of mtDNA, although the mechanism of p53 action is controversial [40], [41]. These studies demonstrate that many transcription factors have additional dynamic, non-canonical functions in mitochondria, which may partially reflect mitochondria-nucleus interaction.
    Acknowledgements This work was financially supported by 2013 program of Key Laboratory of National Health and Family Planning Commission and by the Natural Science Foundation of China (nos. 81270552 and 81273255).
    Introduction The lower gastrointestinal (GI) system is the center of nutrient AP1903 and the first line of defense against pathogens in the lumen. Previous studies from our laboratory and others have shown that moderate exercise has a protective effect against stress or GI-disease-induced gut barrier dysfunction.2, 3 However, other studies have shown that heavy or strenuous exercise disrupts the intestinal immune homeostasis, thus increasing circulating bacteria, which can lead to whole-body inflammation.4, 5 Exercise decreases the splanchnic blood flow in both humans and rodents.6, 7 Splanchnic ischemia induces GI hypoperfusion, which increases the level of tissue hypoxia in the abdominal organs. Hypoxia-inducible factor (HIF) is pivotal in the transcriptional response to hypoxia. HIF is composed of a hypoxia-inducible α subunit and a constitutively expressed β subunit. In normoxic conditions, the HIFα is degraded through the prolyl hydroxylases (PHDs). Under hypoxic conditions, the activity of AP1903 PHDs is inhibited, resulting in the accumulation of HIFα and initiation of downstream transcription. HIFα has 3 isoforms: the ubiquitous HIF-1α, the tissue-specific HIF-2α and HIF-3α. HIF-1α activates several important signaling pathways related to metabolism and inflammation. However, the HIF-1α protein is unstable in normoxic conditions, with a short half-life of 5 min, which increases the difficulty of in situ and in vivo detection of tissue hypoxia and HIF-1α expression. Using HIF-1α luciferase reporter mice, we recently found that a single bout of moderate exercise could increase the abdominal HIF-1α level. In the present study, we hypothesized that exercise could induce tissue hypoxia and HIF-1α accumulation in the lower GI system. Pimonidazole hydrochloride (HCl) was used to detect in situ tissue hypoxia in the organs, which might be affected by the blood flow redistribution. Oxygen-dependent degradation domain (ODD)-Luc mice were also used in this study for detailed in vivo examination of HIF-1α expression. Using 3 exercise models, we find that exercise induced the tissue hypoxia redistribution and an increase in HIF-1α in the small intestine, but these results are not affected by the exercise intensity or duration. These observations, which suggest that HIF-1α may be a potential target for the regulation of GI functions after moderate exercise, may contribute to understanding of the role of exercise interventions in the protection against GI diseases.