Hif-1α/Hsf1/Hsp70 signaling pathway regulates redox homeostasis and apoptosis in large yellow croaker (<i>Larimichthys crocea</i>) under environmental hypoxia

Abstract

Oxygen is an essential molecule for animal respiration, growth, and survival. Unlike in terrestrial environments, contamination and climate change have led to the frequent occurrence of hypoxia in aquatic environments, thus impacting aquatic animal survival. However, the adaptative mechanisms underlying fish responses to environmental hypoxia remain largely unknown. Here, we used large yellow croaker ( Larimichthys crocea ) and large yellow croaker fry (LYCF) cells to investigate the roles of the Hif-1α/Hsf1/Hsp70 signaling pathway in the regulation of cellular redox homeostasis, and apoptosis. We confirmed that hypoxia induced the expression of Hif-1α, Hsf1, and Hsp70 in vivo and in vitro . Genetic Hsp70 knockdown/overexpression indicated that Hsp70 was required for maintaining redox homeostasis and resisting oxidative stress in LYCF cells under hypoxic stress. Hsp70 inhibited caspase-dependent intrinsic apoptosis by maintaining normal mitochondrial membrane potential, enhancing Bcl-2 mRNA and protein expression, inhibiting Bax and caspase3 mRNA expression, and suppressing caspase-3 and caspase-9 activation. Hsp70 suppressed caspase-independent intrinsic apoptosis by inhibiting nuclear translocation of apoptosis-inducing factor (AIF) and disturbed extrinsic apoptosis by inactivating caspase-8. Genetic knockdown/overexpression of Hif-1α and dual-luciferase reporter assay indicated that Hif-1α activated the Hsf1 DNA promoter and enhanced Hsf1 mRNA transcription. Hsf1 enhanced Hsp70 mRNA transcription in a similar manner. In summary, the Hif-1α/Hsf1/Hsp70 signaling pathway plays an important role in regulating redox homeostasis and anti-apoptosis in L. crocea under hypoxic stress.

Apoptosis-inducing factor: a mitochondrial protein associated with metabolic diseases—a narrative review

“…In addition, both hypoxia and hypoxia-inducible factor-1alpha (HIF-1α) overexpression can inhibit the transcriptional activity of the AIF through targeting hypoxia-response element (HRE). AIF is also a target gene for HIF-1α in tumor cells ( 66 , 67 ). In recent years, research on tumor metabolism has become more comprehensive, and researchers have focused more on the correlation between mitochondria and tumors.…”

Different roles of dFOXO and HSF in spatio-temporal dynamics of stress-inducible Hsp70 in lgl-yorkie & lgl-Ras driven epithelial tumours inDrosophila

“…Studies on mammalian cancers have indicated that the hypoxia sensor, HIF-1a (mammalian homolog of Drosophila Sima) activates HSF which in turn causes elevated expression of Hsps in different mammalian cancer cells (Agarwal and Ganesh, 2020; Baird et al, 2006; Luo et al, 2021; Tsuchida et al, 2014). However, our earlier study on lgl - yki OE clonal tumours in Drosophila (Singh et al, 2022) showed that their progression and transformation, and the expression of Hsp83 in them was HSF independent.…”

HSF1 activates the FOXO3a–ΔNp63α–CDK4 axis to promote head and neck squamous cell carcinoma cell proliferation and tumour growth

“…It is reported that inhibition of PI3K signalling can suppress HSF1 expression [44] and mutant p53, including R175H, R273H, R249S, and R282W, can promote HSF1 expression [45]. Moreover, HIF1‐α can bind to the HSF1 gene promoter to facilitate HSF1 transcription [46]. Clinical data show that 72% of HNSCC tumours have TP53 mutation and 14% of HNSCC tumours have PIK3CA mutation [1].…”