Abstract
Iron and oxygen deficiencies are common features in pathophysiological conditions, such as ischemia, neurological diseases, and cancer. Cellular adaptive responses to such deficiencies include repression of mitochondrial respiration, promotion of angiogenesis, and cell cycle control. We applied a systematic proteomics analysis to determine the global proteomic changes caused by acute hypoxia and chronic and acute iron deficiency (ID) in hippocampal neuronal cells. Our analysis identified over 8600 proteins, revealing similar and differential effects of each treatment on activation and inhibition of pathways regulating neuronal development. In addition, comparative analysis of ID-induced proteomics changes in cultured cells and transcriptomic changes in the rat hippocampus identified common altered pathways, indicating specific neuronal effects. Transcription factor enrichment and correlation analysis identified key transcription factors that were activated in both cultured cells and tissue by iron deficiency, including those implicated in iron regulation, such as HIF1, NFY, and NRF1. We further identified MEF2 as a novel transcription factor whose activity was induced by ID in both HT22 proteome and rat hippocampal transcriptome, thus linking iron deficiency to MEF2-dependent cellular signaling pathways in neuronal development. Taken together, our study results identified diverse signaling networks that were differentially regulated by hypoxia and ID in neuronal cells.
Highlights
IntroductionOxygen is one of the key factors in the cellular microenvironment that strongly affects energy homeostasis
Our deep proteomic analysis provided new insights into the hypoxia-induced dynamics of metabolic pathways and epigenetic regulations and identified diverse signaling networks that were differentially regulated by hypoxia and iron deficiency (ID) in neuronal cells
hypoxia-inducible factor 1 (HIF1)-a abundance comparing both acute and chronic ID; this was chosen as the treatment condition for hypoxia in the global quantitative analysis
Summary
Oxygen is one of the key factors in the cellular microenvironment that strongly affects energy homeostasis. Low oxygen availability (hypoxia) inhibits the oxidative phosphorylation-mediated energy production and promotes neuronal cell death, contributing to tissue injury in ischemic brain [8]. Studies in the past two decades have established hypoxia-inducible factors (HIF1-a) as a sensor and master regulator of cellular hypoxia-responsive pathways [9,10,11]. Hypoxia condition inhibits the hydroxylation and subsequent rapid degradation of HIF1-a, which leads to its nuclear enrichment and induction of hypoxia-responsive genes. Recent system-wide analyses using transcriptome profiling and protein quantification have further expanded this body of work by uncovering substantial hypoxia-induced changes in gene expression and protein abundances critical for neuroplasticity in neuronal cells and brain tissues [15,16,17]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
