The role of iron in translational regulation
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Abstract
Iron is an essential microelement that functions as a co-factor for enzymes involved in numerous biological processes, including mitochondrial function, DNA replication and repair, electron transport, lipid β-oxidation, and protein translation. Dysregulation of iron metabolism is a hallmark of aging and has been implicated in the development of a wide range of human age-related diseases. However, whether targeting iron homeostasis can be used to promote longer lifespan remains unclear.In this study, we characterized the role of iron homeostasis in regulation of protein translation and its effects on aging, using Saccharomyces cerevisiae as a model organism. We employed genome-wide transcriptome analysis (RNA-Seq) and ribosome profiling to quantify age-dependent changes in transcription and protein translation during replicative lifespan in yeast. Our data revealed that aging in yeast was associated with an up-regulation of genes involved in iron import into the cell, whereas deletion of several members of the iron regulon led to increased longevity. We further demonstrated that defects in the conserved mRNA-binding protein Cth2, which regulates the stability and translation of mRNAs encoding iron-dependent proteins, extended lifespan by alleviating its repressive effects on mitochondrial function.
Additionally, we investigated the effect of iron depletion on protein translation. Our findings uncovered a complex effect of iron deficiency on the regulation of protein synthesis showing how this important nutrient affects protein translation through multiple mechanisms. Specifically, we found that low iron leads to specific downregulation of genes involved in iron-dependent processes, including mitochondrial translation and heme biosynthesis, at the translation level via the activation of Cth1/2. We further showed that iron deficiency affects global protein translation by decreasing the activity of the ribosome recycling factor Rli1. Finally, we identified a novel regulatory mechanism involving antisense long non-coding RNAs, which are activated under iron-depleted conditions to modulate protein translation.
Together, these findings deepened our understanding of how iron regulates protein translation and revealed Cth2 as a promising target for interventions aimed at extending lifespan.
Description
2025