Role of eIF5A in Mitochondrial Function

Abstract

The eukaryotic translation initiation factor 5A (eIF5A) is an evolutionarily conserved protein that binds ribosomes to facilitate the translation of peptide motifs with consecutive prolines or combinations of prolines with glycine and charged amino acids. It has also been linked to other molecular functions and cellular processes, such as nuclear mRNA export and mRNA decay, proliferation, differentiation, autophagy, and apoptosis. The growing interest in eIF5A relates to its association with the pathogenesis of several diseases, including cancer, viral infection, and diabetes. It has also been proposed as an anti-aging factor: its levels decay in aged cells, whereas increasing levels of active eIF5A result in the rejuvenation of the immune and vascular systems and improved brain cognition. Recent data have linked the role of eIF5A in some pathologies with its function in maintaining healthy mitochondria. The eukaryotic translation initiation factor 5A is upregulated under respiratory metabolism and its deficiency reduces oxygen consumption, ATP production, and the levels of several mitochondrial metabolic enzymes, as well as altering mitochondria dynamics. However, although all the accumulated data strongly link eIF5A to mitochondrial function, the precise molecular role and mechanisms involved are still unknown. In this review, we discuss the findings linking eIF5A and mitochondria, speculate about its role in regulating mitochondrial homeostasis, and highlight its potential as a target in diseases related to energy metabolism.

Keywords: OXPHOS; TCA; eIF5A; mitochondria; mitochondrial respiration; spermidine; translation.

Figure 1

Polyamine-hypusine pathway and its pharmacological inhibitors. Spermidine substrate for eIF5A hypusination is obtained by the conversion of the polyamine ornithine in putrescine by the enzyme ornithine decarboxylase (ODC); next, spermidine is synthesized from putrescine by spermidine synthase (SPDS). Alternatively, spermidine is converted in spermine by spermine synthase (SPMS). Hypusine modification of lysine-50 (human) or lysine-51 (yeast) residue of eIF5A occurs by the addition of spermidine via two consecutive enzymatic reactions. First, deoxyhypusine synthase (DHPS) transfers the aminobutyl group of spermidine to the amino group of lysine generating an intermediate substrate, which does not accumulate. Second, deoxyhypusine hydroxylase (DOHH) adds a hydroxyl group and forms the hypusine residue of eIF5A, which confers the activity to the protein. eIF5A post-translational modification can be suppressed by inhibitors of DHPS and DOHH, but also by inhibition of ODC, the rate limiting enzyme for spermidine biosynthesis. Figure processing was carried out using BioRender software.

Figure 2

Distribution of eIF5A-dependent motifs in Saccharomyces cerevisiae mitochondrial proteins. Distribution of the 43 highest-scoring eIF5A-dependent ribosome-pausing tri-peptide motifs [11] in the proteins of the whole yeast genome (a), nuclear-encoded mitochondrial proteins (b), mitochondrial-encoded proteins (c), the tricarboxylic acid (TCA) cycle (d), oxidative phosphorylation (OXPHOS) (e), and in the mitochondrial organization Gene Ontology functional category (f). The table shows the proteins involved in mitochondrial organization with at least one PPP motif. The protein pause index (PPI) is calculated as the sum of the quantitative value of the ribosome pause provoked by depletion of eIF5A in each of the 43 highest eIF5A-dependent tri-peptide motifs [11] found in the amino acid sequence of each protein, and is higher in proteins that are putatively more dependent on eIF5A for their translation.

Figure 3

Cellular funtions of eIF5A and model for its role in maintaining mitochondrial activity. eIF5A is known to be implicated in different cellular processes, although the most relevant and mitochondrial-related of these are represented in the Figure. Bound to ribosomes, hyp-eIF5A facilitates translation elongation at specific motifs [10,11], as well as ER-coupled translation [23,25,26]. In the nucleus, eIF5A helps to export certain mRNAs and proteins [141]. eIF5A plays a controversial role in apoptosis, as it has been defined to be necessary to induce the mitochondrial mediated apoptosis [124,146], but also to lead to cell death when inhibited [133]. Hyp-eIF5A promotes autophagy through the translation of the autophagy factors ATG3 (autophagy-related 3) and TFEB (transcription factor EB) [42,43]. Increasing evidence shows a direct link between hyp-eIF5A and mitochondrial function. In addition to its association with mitochondria [143,144,145,146], some proteins of both the TCA and ETC have been described to be directly or indirectly affected under hyp-eIF5A inhibition [126,147]. It has also been proposed that hyp-eIF5A could mediate mitophagy through ATG7 (Autophagy Related 7), Pink1 (the mitophagy-associated PTEN-induced putative kinase), and Park (the E3 ubiquitin ligase Parkin) proteins [170]. Other proteins involved in the mitochondrial transport of nuclear-encoded proteins and mitochondrial organization are considered as putative eIF5A targets (Figure 2). Among these, the mitochondrial inner-membrane integral proteins Yta12 (protease of the Yta12/Afg3 complex and yeast homolog of human AFG3L2), and Tim50 (essential subunit of the TIM23 complex and yeast homolog of human TIMM50) contain long polyproline stretches in their amino acids sequences, suggesting a possible dependence on eIF5A for their translation and, thus, a possible link between hyp-eIF5A and mitochondrial function. Figure processing was carried out using BioRender software.