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Open access peer-reviewed chapter

Multiple Layers of Gene-Expression Regulatory Mechanisms during Fermentation and Respiration

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Sachiko Hayashi

Submitted: 30 September 2023 Reviewed: 19 October 2023 Published: 12 December 2023

DOI: 10.5772/intechopen.1003912

New Advances in <em>Saccharomyces</em> IntechOpen
New Advances in Saccharomyces Edited by Antonio Morata

From the Edited Volume

New Advances in Saccharomyces

Antonio Morata, Iris Loira, Carmen González and Carlos Escott

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Abstract

Saccharomyces cerevisiae is widely used as a model organism for eukaryotic cells and generally prefers fermentation rather than respiration even under an aerobic environment. Only when glucose is exhausted, S. cerevisiae switches to aerobic respiration via massive reprogramming of gene expression accompanying that. These gene-expression changes are not simply achieved by the transcriptional level, rather multiple post-transcriptional regulatory steps are also involved. This chapter outlines how budding yeast cells coordinate energy metabolisms based on gene expression, with a focus on the intricate interplay of multiple post-transcriptional regulatory mechanisms. Especially, it includes the roles of RNA-binding proteins as well as non-coding RNAs for post-transcriptional regulations.

Keywords

  • gene expression
  • glucose
  • fermentation
  • respiration
  • mitochondria
  • post-transcription
  • signaling
  • RNA-binding protein
  • non-coding RNA

1. Introduction

Saccharomyces cerevisiae, commonly known as baker’s yeast (referred to hereafter as yeast), is among the earliest eukaryotic organisms to be domesticated by humans. This unicellular microorganism serves as an excellent eukaryotic model for the elucidation of fundamental cellular processes, gene expression, and plays a pivotal role in various biotechnological applications [1].

A fermentable sugar, glucose, is the preferred carbon and energy source, while concurrently serving as a signaling molecule [2, 3]. When yeasts are cultured in glucose-rich media under aerobic conditions, they predominantly employ glucose metabolism through glycolysis, yielding pyruvate as the primary product. Following glucose depletion, the fermented ethanol emerges as a carbon source, initiating a transition to respiration. This transformative metabolic process, known as a diauxic shift, unfolds in tandem with a substantial reconfiguration of gene expression, leading to dynamic upregulation including mitochondrial biogenesis and its functional capacities [4, 5, 6].

Glucose fermentation has superior catalytic efficiency compared to respiration in terms of adenosine triphosphate (ATP) production per unit of protein mass [7]. Conversely, respiration yields a tenfold increase in ATP per glucose molecule [8]. The equilibrium between respiration and fermentation is a pivotal determinant for unicellular survival [9]. Further, the oxidative fermentation or the Crabtree effect [10, 11], grants yeast an ecological advantage by allowing it to swiftly use glucose and produce ethanol, which possesses antiseptic properties [12].

This chapter overviews yeast metabolic systems, which are meticulously regulated through multiple steps at transcriptional and post-translational levels. It encompasses well-established signaling cascades and the regulation of nuclear-encoded mitochondrial gene expression, which interact with and are regulated by RNA-binding proteins and/or non-coding RNAs.

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2. Metabolic arrangements: transitions between fermentation and respiration

Yeast has evolved efficient glucose utilization, employing both respiration and fermentation pathways to generate ATP from glucose. Both processes start with glycolysis, producing two molecules of pyruvate and ATP per glucose molecule. In the fermentation process, pyruvate is subsequently metabolized into ethanol. While this process does not yield additional ATP, it recycles nicotinamide adenine dinucleotide (NAD+) consumed during glycolysis, producing oxygen-independent ATP. In contrast, respiration involves the complete oxidation of pyruvate to CO2 through the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS), yielding additional ATP in the presence of oxygen. Crabtree-positive yeasts, such as S. cerevisiae, favor fermentation over respiration when glucose levels are high, producing ethanol as a byproduct. This metabolic strategy allows them to simultaneously engage in both fermentation and respiration when oxygen and glucose levels are abundant [9, 11]. Although the ethanol accumulating in the environment can be reutilized for ATP generation once glucose is depleted [13], it yields fewer ATP molecules than the direct oxidation of pyruvate due to the energy requirement for synthesizing acetyl-CoA from ethanol, which consumes ATP. As the rate of ATP production increases, ATP-consuming processes, such as ribosome and protein synthesis, to some extent, increasingly impose constraints on growth [14, 15]. Metabolic systems and shifts in the utilization of metabolic pathways can be considered as an array of constraints that depend on the conditions within the framework of cellular economics [9]. Transitions between energy metabolic pathways are observed in various metabolic systems, including tumor cells and bacteria, as well as yeast [9, 11, 16]. Sustaining an optimal metabolic system is a crucial point for the survival or demise of many living organisms.

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3. Molecular and signaling aspects of yeast energy metabolic pathways

Glucose serves as a fundamental messenger molecule, playing a dual role as both an energy source and a signal for optimal growth conditions in cellular machinery. Yeasts, in particular, utilize glucose for this purpose. When the external glucose concentration exceeds 0.8 mM, yeast undergoes a transition into a mixed respiro-fermentative metabolism, resulting in ethanol production [17]. This shift underscores that the regulation between fermentation and respiration primarily corresponds to the sugar level [4]. Therefore, it is unsurprising that glucose plays a key element in shaping growth rate, fermentation capacity, and stress resistance [2, 18].

Multiple distinct pathways participate in responses to glucose. Some involve glucose interactions with cell surface receptors, while others require glucose import into the cell. These frequently utilized cascades can be classified into the following five signaling pathways: Ras-protein kinase A (PKA), Gpr1p–Gpa2p–PKA, the target of rapamycin (TOR)–Sch9p, Snf1p–Mig1p, or Snf3p–Rgt2p [3, 5, 19]. Among these, Ras and TOR, major global nutrient-sensing signal transduction cascades, serve pivotal roles in regulating cell growth in response to nutrient availability [18, 20]. Global glucose repression depends on an intracellular surge of cyclic adenosine monophosphate (cAMP), which activates PKA. Transcription rates significantly decrease upon Ras2p activation, which can occur independently of glucose presence and relies on a cAMP-responsive protein kinase [3, 21].

3.1 Ras–PKA and Gpr1p–Gpa2p–PKA

Ras, a guanine nucleotide-binding protein with seven transmembrane domains, activates adenylyl cyclase in its GTP-bound state. The addition of glucose to cells increases the level of GTP-bound Ras, resulting in an elevation of intracellular cAMP and subsequent activation of PKA [3, 21]. The PKA catalytic subunits, encoded by TPK1, TPK2, and TPK3, phosphorylate various proteins involved in metabolism and transcription. Consequently, a significant number of genes exhibit a reduction in transcription rate upon Ras2p activation [21, 22]. However, glucose-repressed genes do not uniformly respond to Ras2p and PKA activation [3]. Genes involved in trehalose or glycogen metabolism, glucose utilization, or ubiquitination exhibit weak or absent responses to Ras2p activation [3].

Gpr1p, a plasma membrane protein (Figure 1), can sense the presence of glucose and/or sucrose and is coupled to Gα protein Gpa2p [23, 24]. This leads to the activation of adenylyl cyclase, resulting in an increase in cAMP concentration [2, 25, 26]. Subsequently, cAMP activates PKA. Therefore, it eventually controls the transcription of genes related to ribosome biogenesis and stress-responsive genes like RIM15, MSN2, and MSN4. It also exerts post-translational regulation on proteins involved in storage carbohydrate synthesis, the glycolytic pathway, and gluconeogenesis [18, 27, 28, 29, 30, 31, 32, 33]. PKA directly phosphorylates and activates glycolytic enzymes Pfk2p and Pyk1p, enhancing glycolysis and showing a positive correlation between PKA activity and glycolytic flux.

Figure 1.

Glucose signaling, facilitated by the small G-proteins Ras and Gpa2p, converges through PKA to stimulate ribosome biogenesis while concurrently suppressing the general stress response. Concurrently, within the TORC1 pathway, the kinase Sch9p plays a crucial role in strengthening the response of the PKA pathway. Dashed lines in the diagram symbolize regulatory interactions, which might not always be direct. See text for details.

3.2 TOR–Sch9p

TOR is a Ser/Thr kinase that was initially identified through yeast’s genetic screening [34]. The TOR proteins assemble into two structurally and functionally distinct complexes known as TOR complex 1 (TORC1) and TOR complex 2 (TORC2), of which only TORC1 is sensitive to rapamycin [35, 36]. The central components of the TOR consist of two TOR kinases paralogs, Tor1p, and Tor2p, along with a phosphate switch composed of the type 2A-related phosphatase Sit4p, TOR kinase phosphorylates Tap42p, and its inhibitor Tip41p [37, 38]. TORC1-dependent signals are mediated via various effector kinases [39].

The vacuolar surface primarily serves as the location for the TORC1 signaling pathway [40]. TORC1 is involved in respiration-induced mitophagy [41, 42]. This type of mitophagy is particularly important in cells that rely on OXPHOS for energy production, as disruptions in mitochondrial respiration can have significant consequences for cellular energy balance and overall cell function [43, 44].

An AGC family Ser/Thr kinase Sch9p is best characterized as the direct substrate of TORC1 [45]. Sch9p is a master regulator of ribosome biogenesis [45, 46, 47]. TORC1 controls all three RNA polymerase (Pol) systems via Sch9p (Figure 1). Pol I is stimulated in a Sch9p-dependent and -independent manner, partly through regulation of the transcription initiation factor Rrn3p [48, 49, 50]. Regarding Pol II, at the large cohort of the ribosome biogenesis and ribosomal protein (RP) genes, at least in part via Sch9p [45, 51]. Further, Sch9p regulates Pol III by phosphorylating and inactivating Maf1p, a conserved repressor of Pol III activity [50, 52, 53, 54, 55, 56]. Consequently, when yeasts grow logarithmically on glucose, ribosome biogenesis proceeds at maximal speed driven by the positive control of TORC1.

In contrast, gradual glucose exhaustion or abrupt withdrawal of glucose triggers a reduction in TORC1-dependent phosphorylation of five residues within the Sch9p C terminus [45, 57], leading to TORC1 inactivity. Inhibition of TORC1 provokes extensive transcriptome changes, reducing ribosomal particles by blocking the transcription of Pol I-dependent rRNA genes, Pol II-dependent RP genes, Pol III-dependent 5S rRNA, and the processing of 35S rRNA [18, 46, 47, 58]. Diminished phosphorylation of Sch9p transforms the Pol III repressor Maf1p from an inactivated to an active state [46, 59, 60]. This, in turn, leads to the suppression of Pol III transcriptome, including various small non-coding RNAs such as transfer RNA (tRNA). Consistent with TORC1’s functions, the absence of Tor1p results in an increase in mitochondrial respiration during glucose-based growth, primarily due to the enhanced translation of mitochondrial DNA (mtDNA)-encoded subunits of the OXPHOS complex. This effect is not observed in cells growing on glycerol [3, 61].

Recent research has shed light on the role of Snf1p–AMPK in fine-tuning TORC1 signaling during glucose starvation. Snf1p temporarily inhibits TORC1 activity by interacting with the phosphatidylinositol-3-phosphate (PI3P) and Kog1p-binding protein Pib2p [62]. This discovery highlights the mutual interaction between TOR and Snf1p, emphasizing their significance in metabolic adaptation.

3.3 Snf1p–Mig1p

The sucrose non-fermenting (Snf1) protein kinase, the yeast ortholog of mammalian AMP-activated S/T protein kinase (AMPK), is a central component of the primary glucose repression pathway responsible for adapting to glucose limitation [63, 64]. It forms a heterotrimeric complex with Snf4p (the regulatory γ-subunit) and one of the three β-subunits, Sip1p, Sip2p, or Gal83p, alongside the catalytic α-subunit, Snf1p [65]. Snf1p is activated under glucose limitation, assisting in energy homeostasis by promoting catabolic processes and inhibiting anabolic ones related to ATP generation and consumption [66]. This Snf1p complex regulates cellular processes through different transcription factors and enzymes [65]. For instance, Mig1p, a transcriptional repressor, controls the expression of genes involved in the metabolism and transportation of alternative carbon sources (e.g., maltose, galactose, sucrose) [67, 68]. Under glucose-rich conditions, Mig1p undergoes dephosphorylation and translocases to the nucleus (Figure 2). Together with the Ssn6p-Tup1p corepressor, it binds to target gene promoters [67, 69, 70]. Concurrently, Snf1p also undergoes dephosphorylation to prevent its nuclear localization in glucose-rich environments [71]. This dephosphorylation process involves protein phosphatase 1 (PP1), Glc7p–Reg1/2p, and possibly Sit4p, in collaboration with the phosphatase Ptc1p [72, 73, 74, 75, 76, 77].

Figure 2.

The interconnected Snf and Rgt glucose signaling networks play a vital role in cellular regulation. The glucose sensor protein Snf3p, working alongside hexose transporters (Hxt), contributes to the yeast cell’s ability to sense extracellular glucose levels. Rgt1p, a transcription factor, governs glucose repression by controlling the expression of genes involved in glucose sensing and metabolism. Meanwhile, the Snf1p kinase and a transcriptional repressor Mig1p also respond to glucose availability. These components form a complex interplay in the yeast glucose signaling network, revealing the sophisticated regulatory mechanisms that govern cellular responses to glucose fluctuations.

3.4 Snf3p-Rgt2p

Two plasma membrane proteins, each composed of 12 transmembrane domains and featuring putative glucose-sensing capabilities, are Snf3p and Rgt2p (Figure 2). They share a resemblance to the Hxt glucose transporter [78], although they lack the capacity for glucose transport [79]. Their primarily role is regulating the expression of the seven main hexose transporters (HXT) genes [78].

Snf3p and Rgt2p act as glucose sensors, modulating the activity of Rgt1p, the transcription factor, in response to low and high glucose levels, respectively [80]. In the absence of glucose, Rgt1p, along with Ssn6p, Tup1p, Mth1p, and Std1p forms a repressor complex that inhibits HXT gene expression by binding to their promoter regions [81, 82, 83, 84, 85, 86]. In high glucose conditions, Std1p and Mth1p relocate to the plasma membrane and undergo phosphorylated by Yck1/2p [87]. These phosphorylations trigger their inactivation and subsequent degradation through the SCF-Grr1p ubiquitin ligase complex [88, 89]. Consequently, Rgt1p becomes hyperphosphorylated and dissociates from HXT promoters, activating HXT gene expression [88]. Microarray data demonstrates fluctuations in HXT gene expression in response to the presence of glucose and/or other carbon sources, emphasizing the efficiency and sensitivity of the pathway [79, 90].

For more in-depth information on each cascade, comprehensive reviews are available [3, 18, 27, 79, 91].

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4. Mitochondria: the central organelle of energy metabolism

Mitochondria, often referred to as the “powerhouses” of the cell, are essential organelles for both fermentation and respiration. At the diauxic shift, the mitochondrial volume expands concomitantly with the upregulation of Krebs cycle enzymes and respiratory complexes replete with abundant heme and Fe–S centers. Mitochondria are not discrete or autonomous entities; instead, they form highly dynamic and interconnected networks, and their biogenesis and structure are strongly influenced by the cell’s requirements [92, 93]. A classical targeting pathway for nuclear-encoded mitochondrial proteins uses mitochondrial targeting sequences (MTS) mainly located on their N-terminus [94, 95, 96], whereas approximately one-half of mRNAs for nuclear-encoded mitochondrial mRNAs are transported to the mitochondrial surface, and translated locally [97, 98, 99, 100]. Proximity-specific ribosome profiling targeting the tagged ribosomes on the mitochondrial surface showed highly enrichment of nuclear-encoded mitochondrial mRNAs, especially those encoding proteins in the mitochondrial inner membrane [101]. Cryo-electron cryotomography (CryoET) revealed active cytosolic ribosomes attach to the mitochondrial outer membrane and interact with the TOM complex [102]. The cytosolic translation of nuclear-encoded mitochondrial mRNAs and mitochondria indeed closely interact with each other.

4.1 Gene expression strategies for mitochondrial proteins

Mitochondria originated through the permanent integration of purple non-sulfur bacteria [103]. Throughout evolution, the majority of genes originally present in ancient bacteria have been transferred to nuclear DNA. Simultaneously, the genetic code within mitochondria has diverged from the conventional genetic code, resulting in significant differences in codon utilization between these two systems [104, 105]. In yeast today, mtDNA encodes only eight proteins, primarily associated with the OXPHOS system. Over 99% of mitochondrial proteins are instead encoded by the nuclear genome.

Under fermentable conditions, it is often assumed that nuclear-encoded mitochondrial genes are completely inactive due to subdued mitochondrial biogenesis and function. However, in reality, these nuclear-encoded mitochondrial genes remain transcriptionally active but subsequently undergo translational repression and/or rapid mRNA degradation [106, 107, 108]. Conversely, when exposed to respiratory conditions, there is a substantial upregulation of nuclear-encoded mitochondrial mRNAs, followed by increased translation to support mitochondrial biogenesis and enhance oxidative catabolism of carbon substrates. This orchestrated coordination between genomic and mitochondrial gene expression, along with the accurate sorting of nuclear-encoded mitochondrial proteins, is essential for maintaining optimal mitochondrial function [95, 109, 110, 111]. Disruptions in this process, such as the abnormal buildup of mitochondrial precursors in the cytosol leading to mitochondrial precursor over-accumulation stress (mPOS), or mitochondrial dysfunction, can activate a cytosolic proteostasis system [112, 113].

4.2 Iron: a vital element for mitochondrial function

Mitochondria continuously synthesize heme and Fe/S clusters while also facilitating amino acid and lipid metabolism [114, 115, 116]. Iron availability is essential for mitochondrial function and significantly impacts cellular metabolic responses to changes in carbon availability. Interestingly, yeast can survive OXPHOS defects and even complete loss of mtDNA but not disruption of mitochondrial Fe/S assembly, which proves to be fatal [114, 116, 117]. This is because the mitochondrial iron-sulfur cluster (ISC) assembly machinery is essential for the biogenesis of all cellular Fe/S proteins, including those in the cytosol and nucleus, which are involved in DNA maintenance and protein translation [114, 118].

Because iron is essential for cellular processes, when it is scarce, yeast employs Cth2p, an RNA-binding protein induced during iron starvation, to manage iron resources efficiently. Cth2p has a dual role: it suppresses non-essential iron consumption while promoting critical iron-dependent activities, including the assembly of ribonucleotide reductase (RNR) when iron is limited. Cth2p also inhibits mRNAs with AU-rich elements (ARE), mainly those related to iron metabolism and utilization, affecting pathways such as the TCA cycle, lipid biosynthesis, amino acid synthesis, and cofactor production. Additionally, Cth2p prevents excess iron accumulation in vacuoles by degrading mRNAs responsible for iron transport, including CCC1 [119, 120]. CTH2 paralog, CTH1, functions during iron sufficiency and is regulated by Aft1/2p transcription factors [119, 121]. Aft1/2p control iron-responsive genes at the transcriptional level, and their activity is negatively regulated by Cth2p [122, 123, 124]. These mechanisms collectively ensure yeast cells adapt to changing iron conditions and maintain iron homeostasis. A partial list of genes upregulated or downregulated by Cth2p under iron depletion is presented in Table 1.

GeneFunction
HXK1Hexokinase isoenzyme 1
HXT7High-affinity glucose transporter
HXT6High-affinity glucose transporter
SOL46-phosphogluconolactonase
PGM2Phosphoglucomutase; catalyzes the conversion from glucose-1-phosphate to glucose-6-phosphate
HSP31Methylglyoxalase that converts methylglyoxal to D-lactate; involved in diauxic shift and stationary phase survival
HPF1Haze-protective mannoprotein
GPH1Glycogen phosphorylase required for the mobilization of glycogen
GSY1Glycogen synthase; expression induced by glucose limitation
IGD1Cytoplasmic protein that inhibits Gdb1p glycogen debranching activity
ALD3Cytoplasmic aldehyde dehydrogenase
ARG3Ornithine carbamoyltransferase
OM45Mitochondrial outer membrane protein
COX5BSubunit Vb of cytochrome c oxidase
HSP12Plasma membrane protein involved in maintaining membrane organization
COS8Endosomal protein involved in turnover of plasma membrane proteins
REC104Forms a complex with Rec102p and Spo11p necessary during the initiation of recombination
MSC1Mutant is defective in directing meiotic recombination events to homologous chromatids
YHR087WInvolved in RNA metabolism
FIT1Cell wall mannoprotein involved in siderophore-Fe uptake
FIT2Cell wall mannoprotein involved in siderophore-Fe uptake
HMX1Heme binding peroxidase involved in reutilization of heme Fe
CIT1Citrate synthase
CIT3Mitochondrial isoform of citrate synthase
ACO1Mitochondrial aconitase, Fe-S cluster protein
KGD1Alpha-ketoglutarate dehydrogenase
KGD2Dihydrolipoyl transsuccinylase
SDH2Succinate dehydrogenase (ubiquinone) Fe-S cluster subunit
SDH4Succinate dehydrogenase membrane anchor heme-binding subunit
COX4/6/8/9Subunit of cytochrome c oxidase
COQ6Flavin-dependent monooxygenase, ubiquinone biosynthesis
RNR2/4Ribonucleotide-diphosphate reductase
CCC1Transporter that mediates vacuolar Fe storage
RLI1RNase L inhibitor, Fe-S cluster protein
GLT1NAD+-dependent glutamate synthase (GOGAT)
CCP1Mitochondrial cytochrome-c peroxidase
FET3Ferro-O2-oxidoreductase

Table 1.

A subset of genes upregulated or downregulated by Cth2p under iron depletion. Genes exhibiting upregulation include HXK1 to YHR087W, while those undergoing downregulation comprise FIT1 to CCP1. FET3 serves as an example of a Cth2p-independent expression gene.

Comprehensive reviews with more in-depth information mitochondrial protein sorting, iron homeostasis are available [114, 119, 120, 125, 126, 127].

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5. Post-transcriptional gene expression regulation amid dynamic glucose changes

Gene expression is a multifaceted process that goes beyond mere transcriptional regulation, encompassing intricate post-transcriptional control mechanisms. It is not solely determined by transcriptional status; rather, it involves a complex interplay of factors. To optimize their growth conditions, cells undergo adaptations by adjusting their energy requirements through the modulation of vital metabolic enzymes, frequently accomplished via allosteric binding or post-translational modifications [128, 129, 130]. These alterations in protein abundance and interactions significantly impact cellular phenotypes, as demonstrated in proteome analyzes under various conditions [131, 132, 133, 134]. Stringent regulation of mRNA translation and degradation is also crucial for eukaryotic cells to manage their diverse protein repertoire. In particular, this regulation becomes critical in response to glucose depletion or a diauxic shift [135, 136].

Glucose depletion triggers a swift and substantial halt in protein synthesis, which can be rapidly reversed upon glucose replenishment [137]. Additionally, this glucose depletion induces the formation of mRNA processing bodies (P-bodies), which act as central hubs where components of the 5–3′ mRNA decay pathway converge [138, 139, 140]. This compartmentalization of mRNAs in the cytosol potentially leads to translational repression and the degradation of specific mRNAs (although it has not been definitively proven). This phenomenon allows for a reduction in energy consumption while, at the same time, enabling the rapid translation of specific mRNAs. This facilitates the production of proteins necessary for adaptation [138, 141, 142, 143]. P-bodies indeed exclude translational machineries, including ribosomal components [144]. This specific response can significantly impact gene expression on a large scale. Further, during a diauxic shift, essential core components of P-bodies, Dhh1p and Pat1p, known for their roles as mRNA decapping activators and translational repressors, undergo a change in their intracellular localization. They shift from being excluded from polysomes in rapidly growing cells to co-localizing with polysomes [145].

Many aspects regarding P-bodies still remain obscure [143], but cells strategically employ adaptive mechanisms to dynamically regulate mRNA translation and degradation to manage the cellular protein repertoire. These processes are particularly important during glucose depletion and diauxic shifts. The formation of P-bodies and/or the dynamic behavior of core components such as Dhh1p and Pat1p would ensure the cell’s survival and growth in response to changing environmental conditions.

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6. tRNA: a dynamic player of protein synthesis and cellular adaptation

tRNA is a classical small non-coding RNA present universally in living organisms. It plays a fundamental role in translation, along with the ribosome [146]. The primary function of tRNA, transferring amino acids into ribosomes, is to guarantee the precise integration of amino acids into proteins. Alternations in nutrient availability, such as shifts in glucose levels, can impact tRNA expression and their modifications, thereby exerting a profound influence on the efficiency of protein synthesis for a diverse array of proteins.

6.1 tRNA movement

In rapidly growing yeasts, tRNAs account for approximately 15% of the total cellular RNAs [147]. The availability of tRNAs positively correlates with codon utilization, influencing the usage of corresponding codons and vice versa [148]. This reciprocal evolutionary process, linking tRNA abundance and codon usage, results in variations in tRNA gene copy numbers among organisms and tRNA species sharing the same anticodon identity [148, 149]. Yeast harbors 275 nucleonic tRNA genes distributed across 16 chromosomes, representing 42 tRNA species [149, 150]. All tRNA genes are typically actively transcribed, and they encompass various types of tRNAs, including modified variants [146, 151]. These tRNAs are essential for the accurate decoding of the genetic code and maintaining precise cellular proteostasis [152, 153].

Yeast’s mtDNA encodes a complete set of tRNAs (24 tRNA species) required for mitochondrial translation within the organelle [105]. However, two cytosolic tRNAs, tRNALysCUU [154] and tRNAGln [155], are imported into mitochondria, potentially playing a role in stress response. In the case of tRNALysCUU, cells use a unique interaction mechanism with the mitochondrial outer membrane-attached glycolytic enzyme enolase [105]. This interaction induces a conformational change in tRNALysCUU, increasing its affinity for another protein factor, pre-mitochondrial lysyl-tRNA synthetase (preMsk1p), ultimately facilitating its co-import into the mitochondrial matrix [156]. Since the majority of mitochondrial proteins are encoded by the nuclear genome, cytosolic translation involving nuclear-encoded tRNAs significantly influences mitochondrial function. Mutants with impaired function of tRNAGlnUUG or tRNALysUUU exhibit inappropriate activation of various starvation responses during rapid growth. These responses involve the upregulation of genes related to glucose and nitrogen catabolism, along with premature and inadequate activation of autophagy. These effects can be alleviated by overexpressing tRNAGlnUUG or tRNALysUUU, which lack specific modifications [157].

6.2 Balancing act: tRNA dynamics in response to cellular stress

tRNAs are very dynamic, continually shuttling between the nucleus and cytosol throughout their entire life. Approximately one-fifth of total tRNA genes (61 of 275) in yeast, contain a single intron with variable lengths ranging from 14 to 60 nucleotides [149, 158]. Intriguingly, these introns consistently occupy the canonical position, precisely one nucleotide 3′ from the anticodon. These intron-containing tRNA genes transcribe precursor tRNA (pre-tRNA) with the intron sequence forming an A-I pair with anticodon nucleotides. This A-I interaction disrupts the crucial codon-anticodon binding during translation [146, 159, 160]. Thus, tRNA splicing is a vital process to address this issue, for intron-containing pre-tRNAs. However, unlike in mammals, yeast tRNA splicing occurs at the mitochondrial periphery due to the presence of the tRNA splicing SEN complex, which is located in the mitochondrial outer membrane [146, 161]. Consequently, intron-containing pre-tRNAs are transported to the mitochondrial membrane for splicing, and some are subsequently re-imported into the nucleus post-splicing [146].

In the case of mature tRNA, they also show bidirectional movement between the cytoplasm and nucleus [146]. This movement is tightly regulated and responsive to various cellular conditions and signals (Figure 3). In specific instances, mature tRNAs re-enter the nucleus following their cytoplasmic function. Although the reasons for this re-import are not always fully elucidated, it is possibly linked to quality control mechanisms or other regulatory processes [162]. This bidirectional trafficking of mature tRNAs allows cells to finely tune translation processes in response to changing conditions and to maintain the precision of protein synthesis. Thus, it emphasizes the dynamic nature of tRNA trafficking, which would contribute to the accurate and adaptable synthesis of proteins in the cell [146].

Figure 3.

Fine-tuning of tRNA dynamics in response to nutrient stress. tRNAs traverse between the nucleus and cytosol. This bidirectional movement is particularly crucial during varying cellular states, such as in nutrient-rich (fed) and nutrient-depleted (starved) conditions. Within the nucleus, tRNAs not only undergo transcription but also intricate maturation processes, including essential base modifications. Concurrently, in the cytosol, tRNAs actively engage in translation processes, fulfilling their indispensable role in protein synthesis. Under specific stress conditions, such as nutrient or glucose depletion, tRNAs are transported into the nucleus, deviating from cytosolic translation. This adaptive behavior, where tRNAs modulate both their localization and function in response to nutrient availability, underscores their critical involvement in cellular processes and protein synthesis.

Remarkably, under glucose depletion, exposure to non-fermentable carbon sources such as glycerol, or in response to certain stressors, tRNA may accumulate in the nucleus [146, 163]. This sequestration of tRNA in the nucleus serves to isolate it from the cytoplasmic protein synthesis machinery, potentially serving as a mechanism to reduce protein synthesis globally [164, 165]. However, significant nuclear accumulation of cytoplasmic tRNAs does not necessarily result in a widespread inhibition of translation [166, 167]. Instead, the decrease in cytoplasmic tRNA levels during stress may involve the regulation of nuclear-cytoplasmic tRNA shuttling or changing tRNA transcription [165]. For instance, in maf1∆ cells, intron-containing pre-tRNAs can accumulate in the nuclei, regardless of whether these mutant cells are cultured in glucose-rich or non-fermentative carbon sources. This accumulation appears to be due to transcriptional derepression in the absence of Maf1p, a general-negative transcriptional regulator of Pol III [146, 168]. Thus, tRNA’s dynamics, trafficking across cellular compartments, would be a fundamental element in the finely tuned orchestration of protein synthesis, enabling cells to adapt effectively to shifting environmental conditions.

Comprehensive reviews with more in-depth information on tRNA are available [146, 169, 170, 171, 172].

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7. Multifaceted regulator: rNA-binding protein Puf3p

Puf3p, a Pumilio homolog RNA-binding protein, is a well-known regulator of nuclear-encoded mitochondrial mRNAs [173, 174, 175]. Global analysis showed that Puf3p physically associates with 220 transcripts at least, and more than 70% of which are nuclear-encoded mitochondrial mRNAs [176]. Multiple multi-omics studies have consistently confirmed Puf3p’s binding specificity to nuclear-encoded mitochondrial mRNAs [177, 178, 179]. However, PAR-clip [178] and RIP-seq [179] have also identified numerous non-mitochondrial mRNAs as targets of Puf3p. Therefore, while Puf3p significantly influences the regulation of nuclear-encoded mitochondrial mRNAs, it also exerts a broader influence on gene expression associated with mitochondrial functions.

7.1 Molecular basis of Puf3p-RNA interaction: Structural analyzes and binding specificity determinants

Puf3p is comprised of eight Puf repeats, each composed of three α-helices, with neighboring repeats forming a crescent shape [180, 181, 182]. X-ray crystallography has revealed that three amino acid residues within each Puf repeat directly contact a single RNA base, determining binding specificity [182, 183, 184, 185, 186, 187, 188]. The Puf3p repeat domain (Puf3-RD) is sufficient to modulate mRNA metabolism and physically interacts with target mRNAs, exemplified by its binding to the 3′-UTR of COX17 mRNA [189, 190]. The consensus Puf3p binding sequence on target mRNAs has been identified as an 8-nt UGUANAUA motif [176, 191, 192], which generally follows the pattern of PUF proteins binding to an 8-nt sequence with UGU(A/G) at the 5′ end and variable 3′ sequences specific to individual Puf proteins [176, 186, 193, 194]. The presence of cytosine at the second position from the Puf3p binding sequence is crucial for Puf3p-RNA-binding in vitro and biological activity in vivo [182]. Further, the N-terminal part of a PUF domain, responsible for recognizing the 3′ region of the Puf3p site, appears to be more flexible in accommodating target-nucleotide mutations compared to the C-terminal part [195, 196]. Indeed, some PUF proteins exhibit broader specificity by excluding certain undesirable nucleotides [188, 197]. Achieving an equilibrium between the individual binding specificity of each repeat and the total binding affinity to target mRNAs is a determinant for PUF proteins [196]. Three-hybrid analysis revealed that the N-terminal part of the PUF domain is more tolerant of combinatorial mutations in target nucleotides than the C-terminal part [196].

7.2 Multifaceted role of Puf3p in yeast physiology

Yeast Puf3p deletion mutants result in slow growth in respiratory media [176, 198], impair mitochondrial motility and biogenesis [198, 199], alter cellular oxidative stress tolerance and the glutathione redox state [200], and increase cellular oxygen consumption in a growth-dependent manner [201]. Under fermentation, Puf3p destabilizes its target mRNAs by promoting deadenylation and negatively regulates mitochondrial biogenesis [107, 108, 176, 190, 191, 201, 202, 203]. In agreement with its repressive roles in glucose-rich media, Puf3p’s abundance drastically decreases during the diauxic shift [199]. However, Puf3p associates with actively translating polysomes upon glucose depletion and promotes mitochondrial biogenesis [198, 204], indicating its bidirectional functions. These dual functions of Puf3p are regulated by phosphorylation via casein kinase Hrr25p [198, 205]. Mutations in the PUF3 gene, such as PUF3(24A), act dominantly negative and even more strongly inhibit cell growth upon the diauxic shift than the complete deletion of PUF3 [198]. Moreover, phosphorylation of Puf3p potentially influences its activity, and Puf3p-driven regulation at the translational level could enable a more rapid response of mitochondrial biogenesis to fluctuations in glucose availability compared to transcriptional regulation [9]. Remarkably, despite not being a canonical transcription factor, Puf3p has also been implicated in the regulation of genes involved in respiration, along with the HAP2/3/4/5 DNA-binding complex [176, 206].

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8. Conclusions

With its remarkable adaptability in metabolism and precision in gene regulation, yeast serves as a captivating model organism that holds significant implications for biotechnology and deepens our understanding of fundamental cellular intricacies. Its ability to expertly navigate the delicate equilibrium between glucose utilization, fermentation, and respiration underscores the core principles of cellular economics, which are vital for the survival and prosperity of all living organisms.

Furthermore, yeast’s intricate mechanisms for controlling post-transcriptional gene expression, involving processes such as mRNA processing, the dynamic behavior of tRNA, and the influence of RNA-binding proteins like Puf3p, exemplify an evolved strategy that enables cells to adapt to ever-changing environmental challenges rapidly. These dynamic processes serve as the linchpin for preserving cellular proteostasis, ensuring the precise and adaptable synthesis of proteins that play a pivotal role in sustaining and nurturing the growth of life.

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Acknowledgments

This work was supported by JSPS KAKENHI Grant number JP20K06491 to S. H.

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Abbreviations

ATP

adenosine triphosphate

NAD+

nicotinamide adenine dinucleotide

TCA

tricarboxylic acid

OXPHOS

oxidative phosphorylation

PKA

protein kinase A

TOR

target of rapamycin

cAMP

cyclic adenosine monophosphate

TORC1/2

TOR complex 1/2

Pol

RNA polymerase

RP

ribosomal protein

tRNA

transfer RNA

mtDNA

mitochondrial DNA

PI3P

phosphatidylinositol-3-phosphate

Snf1

sucrose non-fermenting

AMPK

AMP-activated S/T protein kinase

PP1

protein phosphatase 1

HXT

hexose transporters

MTS

mitochondrial targeting sequences

CryoET

cryo-electron cryotomography

mPOS

mitochondrial precursor over-accumulation stress

ISC

iron-sulfur cluster

RNR

ribonucleotide reductase

ARE

AU-rich elements

P-bodies

mRNA processing bodies

pre-tRNA

precursor tRNA

Puf3-RD

Puf3p repeat domain

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Written By

Sachiko Hayashi

Submitted: 30 September 2023 Reviewed: 19 October 2023 Published: 12 December 2023

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