microorganisms Review Iron in Translation: From the Beginning to the End Antonia María Romero 1 , María Teresa Martínez-Pastor 2, * and Sergi Puig 1, *   Citation: Romero, A.M.; Martínez-Pastor, M.T.; Puig, S. Iron in Translation: From the Beginning to the End. Microorganisms 2021, 9, 1058. https://doi.org/10.3390/ microorganisms9051058 Academic Editors: Yoav Arava and Ayala Shiber Received: 29 April 2021 Accepted: 11 May 2021 Published: 13 May 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Departamento de Biotecnología, Instituto de Agroquímica y Tecnología de Alimentos (IATA), Consejo Superior de Investigaciones Científicas (CSIC), Catedrático Agustín Escardino 7, Paterna, 46980 Valencia, Spain; am.romero@iata.csic.es 2 Departamento de Bioquímica y Biología Molecular, Universitat de València, Doctor Moliner 50, Burjassot, 46100 Valencia, Spain * Correspondence: maria.teresa.martinez@uv.es (M.T.M.-P.); spuig@iata.csic.es (S.P.) Abstract: Iron is an essential element for all eukaryotes, since it acts as a cofactor for many enzymes involved in basic cellular functions, including translation. While the mammalian iron-regulatory protein/iron-responsive element (IRP/IRE) system arose as one of the first examples of translational regulation in higher eukaryotes, little is known about the contribution of iron itself to the different stages of eukaryotic translation. In the yeast Saccharomyces cerevisiae, iron deficiency provokes a global impairment of translation at the initiation step, which is mediated by the Gcn2-eIF2α pathway, while the post-transcriptional regulator Cth2 specifically represses the translation of a subgroup of iron- related transcripts. In addition, several steps of the translation process depend on iron-containing enzymes, including particular modifications of translation elongation factors and transfer RNAs (tRNAs), and translation termination by the ATP-binding cassette family member Rli1 (ABCE1 in humans) and the prolyl hydroxylase Tpa1. The influence of these modifications and their correlation with codon bias in the dynamic control of protein biosynthesis, mainly in response to stress, is emerging as an interesting focus of research. Taking S. cerevisiae as a model, we hereby discuss the relevance of iron in the control of global and specific translation steps. Keywords: translation; tRNA modification; yeast; Saccharomyces cerevisiae; iron deficiency 1. Introduction Iron is an indispensable micronutrient for all eukaryotes and most prokaryotes due to its participation as a redox cofactor in fundamental cellular processes, including DNA repli- cation and repair, cellular respiration, photosynthesis, oxygen transport, lipid metabolism, and, importantly, translation, which is the focus of the present review. While ferrous iron (Fe 2+ ) was highly abundant and soluble in the anoxic environments where the first organisms evolved, the rise in oxygen levels in the Earth’s atmosphere compromised the bioavailability of iron, due to its oxidation to ferric iron (Fe 3+ ), which is extremely insol- uble at physiological pH. Therefore, organisms have evolved sophisticated mechanisms to acquire iron and modulate its homeostasis in order to maintain many essential iron- dependent processes. Nonetheless, iron deficiency is the most common nutritional disorder that humans and plants address, with important consequences for human health and the nutritional quality of crops [1,2]. It has been known for years that mitochondria are indispensable for eukaryotic life. This essentiality was first assigned to the multiple iron-dependent metabolic processes that take place in this organelle, including respiration. However, when this question was addressed more profoundly in the eukaryotic model Saccharomyces cerevisiae, which can grow in the absence of mitochondrial DNA, it was discovered that the minimal essential function of mitochondria relied on the biogenesis of cellular iron-sulfur (Fe/S) proteins (reviewed in [3]). Intriguingly, the first essential target of the mitochondrial Fe/S cluster (ISC) assembly system identified was a cytosolic protein, Rli1 (ABCE1 in humans), which is Microorganisms 2021, 9, 1058. https://doi.org/10.3390/microorganisms9051058 https://www.mdpi.com/journal/microorganisms