Abstract
Hypoxia has been associated with several pathological conditions ranging from stroke to cancer. This condition results in the activation of autophagy, a cyto-protective response involving the formation of double-membraned structures, the autophagosomes, in the cytoplasm. In this study, we investigated the cellular mechanisms regulating the autophagy gene Ambra1, after exposure to a hypoxia mimetic, cobalt chloride (CoCl2). We observed that, upon CoCl2 administration, activation of the apoptotic machinery was concomitant with down-regulation of the pro-autophagic factor Ambra1, without affecting transcription. Additionally, co-treating the cells with the caspase inhibitor z-VAD-FMK did not restore Ambra1 protein levels, this implying the involvement of other regulatory mechanisms. Partial re-localization of Ambra1 mRNA to non-translating fractions and cytoplasmic P-bodies was further detected. Thus, in this pseudohypoxic context, Ambra1 mRNA translocation to P-bodies and translational suppression correlated with increased cell death.
Highlights
Multicellular organisms have developed oxygen-sensing systems to maintain oxygen homeostasis, which is essential for survival of the organism [1]
We found that 8 hours after treatment with CoCl2 there is no production of new autophagosomes; instead, the autophagy flux is blocked, leading to LC3II accumulation (Fig 2B)
We observed that Ambra1 protein levels decreased upon prolonged exposure to the hypoxia mimetic CoCl2, without any significant changes in mRNA levels
Summary
Multicellular organisms have developed oxygen-sensing systems to maintain oxygen homeostasis, which is essential for survival of the organism [1]. Hif-1α (Hypoxia-inducible factor alpha) is a transcription factor that is rapidly activated in response to decreased levels of O2; this switches on, in turn, a subset of genes ensuring cell survival in hypoxic conditions [3]. Among the genes controlled by Hif-1α are VEGF (Vascular Endothelial Growth Factor) and EPO (Erythropoietin), both involved in erythropoiesis and angiogenesis to increase oxygen delivery to the hypoxic site [4,5]. Hypoxia generally activates the cyto-protective response of autophagy in a Hif-1α dependent manner [3]. Autophagy is a highly conserved process of self-digestion through the lysosomal pathway. It involves the delivery of cytoplasmic components and organelles to the lysosomes through
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