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Proline metabolism schematic pathways. Gray area indicate fused enzymes that are present in only certain species. Fused P5CSs are found in both animals and plants although fused PutA enzymes are only present in certain prokaryotes. GK: gamma-glutamyl kinase, glu-P: gamma-glutamyl phsophate , GPR: gamma-glutamyl phosphate reductase, GSA: glutamate semialdehyde, P5C: pyrroline-5-carboxylate, P5CDH: P5C dehydrogenase, P5CR: P5C reductase, P5CS: P5C synthase, ProDH: proline dehydrogenase, PutA: proline utilization A.
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Proline dehydrogenase (ProDH), also called proline oxidase (POX), is a universal enzyme in living organisms. It catalyzes the oxidation of L-proline to delta1-pyrroline-5-carboxylate leading to the release of electrons, which can be transferred to either electron transfer systems or to molecular oxygen. ProDH is not only essential for proline catab...
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Context 1
... dehydrogenase (ProDH), also called proline oxidase (POX), is a universal enzyme in living organisms. It catalyzes the oxidation of L-proline to delta1- pyrroline-5-carboxylate leading to the release of electrons, which can be transferred to either electron transfer systems or to molecular oxygen. ProDH is not only essential for proline catabolism but also plays key roles in providing energy, shuttling redox potential between cellular compartments and reactive oxygen species production. Structural analysis of prokaryotic ProDHs already gives some insights into the biochemical activity and biological functions of this enzyme, which can be extended to eukaryotic ProDHs based on sequence similarities. Here we report the most recent investigations on the biochemical and regulation of ProDH at transcriptional, post- transcriptional and translational levels. The biological roles of ProDH in cell homeostasis and adaptation through energetic, developmental, adaptive, physiological and pathological processes in eukaryotes are presented and discussed to create a framework for future research direction. Proline is a proteinogenic secondary amino acid, which plays essential roles not only in primary metabolism but also in redox homeostasis, osmotic adjustment, protection against stress and signaling in all organisms (for review see 1). Proline dehydrogenase (ProDH), also known as proline oxidase (POX), catalyzes the first step in the two-step oxidation of proline in bacteria and eukaryotes (Figure 1). ProDH activity is FAD-dependent and produces delta1-pyrroline-5-carboxylate (P5C), which forms a non- enzymatic equilibrium with glutamate semialdehyde (GSA). P5C dehydrogenase (P5CDH) then converts GSA to glutamate (Figure 1). In most bacteria, ProDH and P5CDH activities are combined in a single bifunctional enzyme known as Proline utilization A (PutA) (2). ProDH is a flavoenzyme in prokaryotes and yeast while P5CDH is an NAD + -dependent reductase (2, 3). Oxidation of proline to glutamate via the intermediate GSA/P5C transfers electrons to mitochondrial electron transfer system by ProDH-FAD complex and forms P5C, which is further oxidized to glutamate by P5CDH, that concomitantly reduces NAD + or NADP + . In contrast to proline oxidation, which takes place in mitochondria in eukaryotes, proline biosynthesis occurs in different compartments according to species. For example, proline is synthesized in mitochondria in animal cells but in cytosol of fungal and plants cells (1, 4, 5). Recently P5C synthase 1 (P5CS1) accumulation has been reported in chloroplast in stressed plants (6). So far, most studies have been focused on the biosynthetic pathway and biological roles of proline itself, but the influence of proline oxidation has been underestimated until recently and remains largely unknown. Oxidation of proline not only contributes to lower the amount of proline in the cell, hence abolishing its protective function, but also generates various molecules such as ATP, reactive oxygen species (ROS), NADH/NADPH+H + and alpha-ketoglutarate (Figure 2). Despite their ubiquity, ProDHs are structurally different with distinct cellular and physiological roles in different species. The aim of this review is to give an overview of what is known about the differences in ProDH structure across kingdoms and to discuss its roles in cell homeostasis adaptation. We therefore collate and compare information on the phylogeny, biochemistry and localization of ProDH in order to understand the physiological consequences of proline oxidation in both prokaryotes and eukaryotes. The organization of ProDH enzymes in organisms from all kingdoms has been clarified with the recent availability of several bacterial genomes and comparative structural analysis of the predicted proteins encoded. With the exception of ProDH from Archaea, which is a divergent enzyme (7), ProDH activity is found in mono-, bi- and tri-functional enzymes. Among prokaryotes, Eubacteria possess all three types of enzymes (Figure 3). Bi- and tri-functional enzymes, called PutA, are membrane- associated proteins with 1000-1300 amino acid residues. PutA from Escherichia coli was the first protein to be crystallized and is believed to function as a homodimer (8). E. coli PutA possesses three functions as revealed by amino acid sequence alignment and crystal structure analysis. A function of regulating transcription of the Put regulon is present in the N-terminal part of the protein, followed by the ProDH and the P5CDH enzymatic domains (Figure 3). Interestingly, eukaryotes possess only monofunctional ProDH enzymes (Figure 3). Structural and spectroscopic analysis of bacterial and yeast ProDHs confirmed the presence of a flavin cofactor bound to the polypeptide (2, 6, 9). This FAD cofactor is also likely to be present in ProDH from animals and plants but to our knowledge this has still to be structurally demonstrated. Protein sequence encoded by ProDH genes from 63 eukaryotic species were aligned to build an unrooted phylogenic tree. The analysis reveals distinct clusters of sequence similarities for ProDH originating from algae, fungi, protozoa, invertebrates, vertebrates and plants. Two ProDH isoforms are found in plants and vertebrates whereas, from the available data, algae, fungi and invertebrates only have a single ProDH copy per genome (Figure 4). In dicotyledonous plants, the two ProDH isoforms, when known, are closely related (75% identities for Arabidopsis thaliana ProDH), in contrast to ...
Context 2
... dehydrogenase (ProDH), also called proline oxidase (POX), is a universal enzyme in living organisms. It catalyzes the oxidation of L-proline to delta1- pyrroline-5-carboxylate leading to the release of electrons, which can be transferred to either electron transfer systems or to molecular oxygen. ProDH is not only essential for proline catabolism but also plays key roles in providing energy, shuttling redox potential between cellular compartments and reactive oxygen species production. Structural analysis of prokaryotic ProDHs already gives some insights into the biochemical activity and biological functions of this enzyme, which can be extended to eukaryotic ProDHs based on sequence similarities. Here we report the most recent investigations on the biochemical and regulation of ProDH at transcriptional, post- transcriptional and translational levels. The biological roles of ProDH in cell homeostasis and adaptation through energetic, developmental, adaptive, physiological and pathological processes in eukaryotes are presented and discussed to create a framework for future research direction. Proline is a proteinogenic secondary amino acid, which plays essential roles not only in primary metabolism but also in redox homeostasis, osmotic adjustment, protection against stress and signaling in all organisms (for review see 1). Proline dehydrogenase (ProDH), also known as proline oxidase (POX), catalyzes the first step in the two-step oxidation of proline in bacteria and eukaryotes (Figure 1). ProDH activity is FAD-dependent and produces delta1-pyrroline-5-carboxylate (P5C), which forms a non- enzymatic equilibrium with glutamate semialdehyde (GSA). P5C dehydrogenase (P5CDH) then converts GSA to glutamate (Figure 1). In most bacteria, ProDH and P5CDH activities are combined in a single bifunctional enzyme known as Proline utilization A (PutA) (2). ProDH is a flavoenzyme in prokaryotes and yeast while P5CDH is an NAD + -dependent reductase (2, 3). Oxidation of proline to glutamate via the intermediate GSA/P5C transfers electrons to mitochondrial electron transfer system by ProDH-FAD complex and forms P5C, which is further oxidized to glutamate by P5CDH, that concomitantly reduces NAD + or NADP + . In contrast to proline oxidation, which takes place in mitochondria in eukaryotes, proline biosynthesis occurs in different compartments according to species. For example, proline is synthesized in mitochondria in animal cells but in cytosol of fungal and plants cells (1, 4, 5). Recently P5C synthase 1 (P5CS1) accumulation has been reported in chloroplast in stressed plants (6). So far, most studies have been focused on the biosynthetic pathway and biological roles of proline itself, but the influence of proline oxidation has been underestimated until recently and remains largely unknown. Oxidation of proline not only contributes to lower the amount of proline in the cell, hence abolishing its protective function, but also generates various molecules such as ATP, reactive oxygen species (ROS), NADH/NADPH+H + and alpha-ketoglutarate (Figure 2). Despite their ubiquity, ProDHs are structurally different with distinct cellular and physiological roles in different species. The aim of this review is to give an overview of what is known about the differences in ProDH structure across kingdoms and to discuss its roles in cell homeostasis adaptation. We therefore collate and compare information on the phylogeny, biochemistry and localization of ProDH in order to understand the physiological consequences of proline oxidation in both prokaryotes and eukaryotes. The organization of ProDH enzymes in organisms from all kingdoms has been clarified with the recent availability of several bacterial genomes and comparative structural analysis of the predicted proteins encoded. With the exception of ProDH from Archaea, which is a divergent enzyme (7), ProDH activity is found in mono-, bi- and tri-functional enzymes. Among prokaryotes, Eubacteria possess all three types of enzymes (Figure 3). Bi- and tri-functional enzymes, called PutA, are membrane- associated proteins with 1000-1300 amino acid residues. PutA from Escherichia coli was the first protein to be crystallized and is believed to function as a homodimer (8). E. coli PutA possesses three functions as revealed by amino acid sequence alignment and crystal structure analysis. A function of regulating transcription of the Put regulon is present in the N-terminal part of the protein, followed by the ProDH and the P5CDH enzymatic domains (Figure 3). Interestingly, eukaryotes possess only monofunctional ProDH enzymes (Figure 3). Structural and spectroscopic analysis of bacterial and yeast ProDHs confirmed the presence of a flavin cofactor bound to the polypeptide (2, 6, 9). This FAD cofactor is also likely to be present in ProDH from animals and plants but to our knowledge this has still to be structurally demonstrated. Protein sequence encoded by ProDH genes from 63 eukaryotic species were aligned to build an unrooted phylogenic tree. The analysis reveals distinct clusters of sequence similarities for ProDH originating from algae, fungi, protozoa, invertebrates, vertebrates and plants. Two ProDH isoforms are found in plants and vertebrates whereas, from the available data, algae, fungi and invertebrates only have a single ProDH copy per genome (Figure 4). In dicotyledonous plants, the two ProDH isoforms, when known, are closely related (75% identities for Arabidopsis thaliana ProDH), in contrast to ...
Citations
... In some bacteria such as Escherichia coli, a DNA-binding domain is also present in the N-ter part of the bifunctional enzyme, which enables EcPutA to act as a transcriptional repressor of proline utilization genes (Gu et al., 2004). In some bacteria such as Thermus thermophilus, ProDH and P5CDH are monofunctional enzymes, which is also the case in eukaryotes (Tanner, 2008;Servet et al., 2012). OAT is thought to act as a monofunctional enzyme in all kingdoms (You et al., 2012;Anwar et al., 2018). ...
... Arabidopsis possesses two distinct and non-redundant isoforms of ProDH, ProDH1 and ProDH2, which share 75% sequence identity (Servet et al., 2012). In addition, Arabidopsis has one isoform each of P5CDH and OAT (Deuschle et al., 2001;Funck et al., 2008). ...
Proline dehydrogenase (ProDH) and pyrroline-5-carboxylate (P5C) dehydrogenase (P5CDH) catalyze the oxidation of proline into glutamate via the intermediates P5C and glutamate-semialdehyde (GSA), which spontaneously interconvert. P5C and GSA are also intermediates in the production of glutamate from ornithine and α-ketoglutarate catalyzed by ornithine δ-aminotransferase (OAT). ProDH and P5CDH form a fused bifunctional PutA enzyme in Gram-negative bacteria and are associated in a bifunctional substrate channelling complex in Thermus thermophilus, but the physical proximity of ProDH and P5CDH in eukaryotes has not been described. Here we report evidence of physical proximity and interactions between Arabidopsis ProDH, P5CDH and OAT in the mitochondria of plants during dark-induced leaf senescence when all three enzymes are expressed. Pairwise interactions and localization of the three enzymes were investigated using bimolecular fluorescence complementation (BiFC) with confocal microscopy in tobacco and sub-mitochondrial fractionation in Arabidopsis. Evidence for a complex composed of ProDH, P5CDH, and OAT was revealed by co-migration of the proteins in native conditions upon gel electrophoresis. Co-immunoprecipitation coupled with mass spectrometry analysis confirmed the presence of the P5C metabolism complex in Arabidopsis. Pull-down assays further demonstrated a direct interaction between ProDH1 and P5CDH. P5C metabolism complexes may channel P5C among the constituent enzymes and directly provide electrons to the respiratory electron chain via ProDH.
... Proline dehydrogenase (ProDH) causes the oxidation of L-proline to pyrroline-5-carboxylate and is located in the inner membrane of mitochondria 76 . It has been reported that ProDH protects cellular respiration under stressful conditions, and proline and ProDH reduce the effects of oxidative stress by maintaining NADPH 77,78 . ...
Although the role of long non-coding RNAs (lncRNAs) in key biological processes in animals and plants has been confirmed for decades, their identification in fungi remains limited. In this study, we discovered and characterized lncRNAs in Aspergillus flavus in response to changes in water activity, CO2 concentration, and temperature, and predicted their regulatory roles in cellular functions. A total of 472 lncRNAs were identified in the genome of A. flavus, consisting of 470 novel lncRNAs and 2 putative lncRNAs (EFT00053849670 and EFT00053849665). Our analysis of lncRNA expression revealed significant differential expression under stress conditions in A. flavus. Our findings indicate that lncRNAs in A. flavus, particularly down-regulated lncRNAs, may play pivotal regulatory roles in aflatoxin biosynthesis, respiratory activities, cellular survival, and metabolic maintenance under stress conditions. Additionally, we predicted that sense lncRNAs down-regulated by a temperature of 30 °C, osmotic stress, and CO2 concentration might indirectly regulate proline metabolism. Furthermore, subcellular localization analysis revealed that up-and down-regulated lncRNAs are frequently localized in the nucleus under stress conditions, particularly at a water activity of 0.91, while most up-regulated lncRNAs may be located in the cytoplasm under high CO2 concentration.
... The oxidation of glycerol-3-phosphate by mitochondrial glycerol 3-phosphate dehydrogenase is a major pathway for the transfer of cytosolic reducing equivalents from lipid and carbohydrate metabolism to the mitochondrial electron transport chain. In addition, mtQ accepts electrons from FAD-linked proline dehydrogenase, which is involved in the metabolism of amino acids [45,46]. In the branched mitochondrial respiratory chain of plants, fungi, and some protists, mtQ receives electrons from alternative rotenone-resistant NAD(P)H dehydrogenases located on the outer and inner surfaces of the inner mitochondrial membrane [47,48]. ...
Mitochondrial coenzyme Q (mtQ) of the inner mitochondrial membrane is a redox active mobile carrier in the respiratory chain that transfers electrons between reducing dehydrogenases and oxidizing pathway(s). mtQ is also involved in mitochondrial reactive oxygen species (mtROS) formation through the mitochondrial respiratory chain. Some mtQ-binding sites related to the respiratory chain can directly form the superoxide anion from semiubiquinone radicals. On the other hand, reduced mtQ (ubiquinol, mtQH2) recycles other antioxidants and directly acts on free radicals, preventing oxidative modifications. The redox state of the mtQ pool is a central bioenergetic patameter that alters in response to changes in mitochondrial function. It reflects mitochondrial bioenergetic activity and mtROS formation level, and thus the oxidative stress associated with the mitochondria. Surprisingly, there are few studies describing a direct relationship between the mtQ redox state and mtROS production under physiological and pathological conditions. Here, we provide a first overview of what is known about the factors affecting mtQ redox homeostasis and its relationship to mtROS production. We have proposed that the level of reduction (the endogenous redox state) of mtQ may be a useful indirect marker to assess total mtROS formation. A higher mtQ reduction level (mtQH2/mtQtotal) indicates greater mtROS formation. The mtQ reduction level, and thus the mtROS formation, depends on the size of the mtQ pool and the activity of the mtQ-reducing and mtQH2-oxidizing pathway(s) of respiratory chain. We focus on a number of physiological and pathophysiological factors affecting the amount of mtQ and thus its redox homeostasis and mtROS production level.
... Proline is oxidized in mitochondria by the sequential action of ProDH and P5CDH to release glutamate (Szabados & Savouré, 2010). ProDH is a FAD-dependent enzyme, which catalyses the first and rate-limiting step of proline oxidation to form P5C (reviewed in Servet, 2012), while P5CDH is an NAD-dependent enzyme which converts P5C to glutamate. Hence, by producing FADH 2 and NADH, proline catabolism produces reducing power in the form of FADH 2 and NADH, and potentially fuels mitochondrial respiration (Cabassa-Hourton et al., 2016;Launay et al., 2019). ...
During leaf senescence, nitrogen is remobilized and carbon backbones are replenished by amino acid catabolism, with many of the key reactions occurring in mitochondria. The intermediate Δ1‐pyrroline‐5‐carboxylate (P5C) is common to some catabolic pathways, thus linking the metabolism of several amino acids, including proline and arginine. Specifically, mitochondrial proline catabolism involves sequential action of proline dehydrogenase (ProDH) and P5C dehydrogenase (P5CDH) to produce P5C and then glutamate. Arginine catabolism produces urea and ornithine, the latter in the presence of α‐ketoglutarate being converted by ornithine δ‐aminotransferase (OAT) into P5C and glutamate. Metabolic changes during dark‐induced leaf senescence (DIS) were studied in Arabidopsis thaliana leaves of Col‐0 and in prodh1prodh2, p5cdh, and oat mutants. Progression of DIS was followed by measuring chlorophyll and proline contents for 5 days. Metabolomic profiling of 116 compounds revealed similar profiles of Col‐0 and oat metabolism, distinct from prodh1prodh2 and p5cdh metabolism. Metabolic dynamics were accelerated in p5cdh by one day. Notably, more P5C and proline accumulated in p5cdh than in prodh1prodh2. ProDH1 enzymatic activity and protein amount were significantly down‐regulated in p5cdh mutant at day 4 of DIS. Mitochondrial P5C levels appeared critical in determining the flow through interconnected amino acid remobilisation pathways to sustain senescence. This article is protected by copyright. All rights reserved.
... Some of these advances in AA biochemistry, physiology, and nutrition were highlighted in a special issue of Frontiers in Bioscience-Landmark entitled "Amino Acids in Nu-trition, Health, and Disease" . Its specific topics included: (a) proline metabolism and signaling in parasites, bacteria and cancers [11][12][13][14][15][16]; (b) homeostasis as well as signaling and regulatory roles of AAs [17][18][19][20][21][22][23][24][25][26]; (c) functions of AAs in fetal growth and development [27][28][29]; (d) roles of AAs in intestinal metabolism, growth and health [30][31][32][33][34][35][36][37]; and (e) experimental methods, models, and data analysis [38][39][40][41][42][43][44][45]. ...
... Proline contributes to interactions between microbial pathogens and their hosts through regulating oxidative stress, osmotic stress, cell signaling, and cell metabolism [12][13][14][15]. Thus, much work has been done to determine proline transport and metabolism in microbes and bacteria. ...
... Promastigotes, and Crithidia spp. choanomastigotes, utilize proline as a major metabolic fuel in an age-and substrate-dependent manner [14]. For example, when trypanosomes develop into a procyclic form in the tsetse fly midgut where glucose is scarce, their procyclics make efficient uses of proline as a main energy source. ...
... The two-step pathway of Pro oxidative catabolism to Glu is understood. The mitochondrial enzyme Pro dehydrogenase (ProDH) oxidizes Pro to pyrroline-5-carboxylate (P5C) and likely supplies electrons directly to ubiquinol via its FADH cofactor (Szabados and Savouré, 2010;Servet et al., 2012;Cabassa-Hourton et al., 2016;Launay et al., 2019). In the second step, P5C spontaneously transforms into glutamate-5-semialdehyde, which is oxidized to Glu by mitochondrial P5C dehydrogenase (P5CDH) with the concomitant reduction of NAD + to NADH (Forlani et al., 1997;Verslues and Sharma, 2010;Trovato et al., 2019). ...
Proline (Pro) catabolism and reactive oxygen species production have been linked in mammals and Caenorhabditis elegans, while increases in leaf respiration rate follow Pro exposure in plants. Here we investigated how alternative oxidases (AOXs) of the mitochondrial electron transport chain accommodate the large, atypical flux resulting from Pro catabolism and limit oxidative stress during Pro breakdown in mature Arabidopsis (Arabidopsis thaliana) leaves. Following Pro treatment, AOX1a and AOX1d accumulate at transcript and protein levels, with AOX1d approaching the level of the typically dominant AOX1a isoform. We therefore sought to determine the function of both AOX isoforms under Pro respiring conditions. Oxygen consumption rate measurements in aox1a and aox1d leaves suggested these AOXs can functionally compensate for each other to establish enhanced AOX catalytic capacity in response to Pro. Generation of aox1a.aox1d lines showed complete loss of AOX proteins and activity upon Pro treatment, yet full respiratory induction in response to Pro remained possible via the cytochrome pathway. However, aox1a.aox1d leaves displayed symptoms of elevated oxidative stress and suffered increased oxidative damage during Pro metabolism compared to the WT or the single mutants. During recovery from salt stress, when relatively high rates of Pro catabolism occur naturally, photosynthetic rates in aox1a.aox1d recovered slower than in WT or the single aox lines, showing that both AOX1a and AOX1d are beneficial for cellular metabolism during Pro drawdown following osmotic stress. This work provides physiological evidence of a beneficial role for AOX1a but also the less studied AOX1d isoform in allowing safe catabolism of alternative respiratory substrates like Pro.
... Virtually all organisms catabolize proline using a unique and structurally conserved flavoprotein, proline dehydrogenase (PRODH); and in eukaryotes, this enzyme is associated with the inner mitochondrial membrane where it transfers two electrons to the electron transport chain to produce either ATP or reactive oxygen species (ROS) (Donald et al. 2001;Lee et al. 2003;Servet et al. 2012). PRODH's potential importance in cancer was unknowingly revealed by Vogelstein's group when they identified PIG6 ("p53-induced gene 6") as one of the most strongly upregulated genes by the tumor suppressing protein, p53 (Polyak et al. 1997). ...
Proline dehydrogenase (PRODH) is a mitochondrial inner membrane flavoprotein critical for cancer cell survival under stress conditions and newly recognized as a potential target for cancer drug development. Reversible (competitive) and irreversible (suicide) inhibitors of PRODH have been shown in vivo to inhibit cancer cell growth with excellent host tolerance. Surprisingly, the PRODH suicide inhibitor N -propargylglycine ( N -PPG) also induces rapid decay of PRODH with concordant upregulation of mitochondrial chaperones (HSP-60, GRP-75) and the inner membrane protease YME1L1, signifying activation of the mitochondrial unfolded protein response (UPR mt ) independent of anticancer activity. The present study was undertaken to address two aims: (i) use PRODH overexpressing human cancer cells (ZR-75-1) to confirm the UPR mt inducing properties of N -PPG relative to another equipotent irreversible PRODH inhibitor, thiazolidine-2-carboxylate (T2C); and (ii) employ biochemical and transcriptomic approaches to determine if orally administered N -PPG can penetrate the blood–brain barrier, essential for its future use as a brain cancer therapeutic, and also potentially protect normal brain tissue by inducing mitohormesis. Oral daily treatments of N- PPG produced a dose-dependent decline in brain mitochondrial PRODH protein without detectable impairment in mouse health; furthermore, mice repeatedly dosed with 50 mg/kg N- PPG showed increased brain expression of the mitohormesis associated protease, YME1L1. Whole brain transcriptome (RNAseq) analyses of these mice revealed significant gene set enrichment in N -PPG stimulated neural processes (FDR p < 0.05). Given this in vivo evidence of brain bioavailability and neural mitohormesis induction, N -PPG appears to be unique among anticancer agents and should be evaluated for repurposing as a pharmaceutical capable of mitigating the proteotoxic mechanisms driving neurodegenerative disorders.
... Mammalian PRODH1 catalyzes the oxidation of Lproline to D1-pyrroline-5-carboxylate leading to electron transfer to CoQ [142] (Fig. 6). This intermediate hydrolyzes nonenzymatically to glutamic semialdehyde, which is further oxidized to glutamate in an NAD +dependent reaction catalyzed by ALDH4A1. ...
... Some flying insects like the honeybee (Apis mellifera) have a high proline content in their hemolymph and this is rapidly consumed during flight, possibly providing a rapid energy source at the beginning of a flight. Therefore, proline metabolism is especially important in nutrient stress because proline is available in large amounts from the breakdown of extracellular matrix, particularly the proline-rich collagens, and can under such conditions be used to drive the ETS for ATP production [142]. PRODH activity has been suggested to be an important contributor to cellular ROS production. ...
Coenzyme Q (CoQ, ubiquinone) is the electron‐carrying lipid in the mitochondrial electron transport system (ETS). In mammals, it serves as the electron acceptor for nine mitochondrial inner membrane dehydrogenases. These include the NADH dehydrogenase (complex I, CI) and succinate dehydrogenase (complex II, CII) but also several others that are often omitted in the context of respiratory enzymes: dihydroorotate dehydrogenase, choline dehydrogenase, electron‐transferring flavoprotein dehydrogenase, mitochondrial glycerol‐3‐phosphate dehydrogenase, proline dehydrogenases 1 and 2, and sulfide:quinone oxidoreductase. The metabolic pathways these enzymes are involved in range from amino acid and fatty acid oxidation to nucleotide biosynthesis, methylation, and hydrogen sulfide detoxification, among many others. The CoQ‐linked metabolism depends on CoQ reoxidation by the mitochondrial complex III (cytochrome bc1 complex, CIII). However, the literature is surprisingly limited as for the role of the CoQ‐linked metabolism in the pathogenesis of human diseases of oxidative phosphorylation (OXPHOS), in which the CoQ homeostasis is directly or indirectly affected. In this review, we give an introduction to CIII function, and an overview of the pathological consequences of CIII dysfunction in humans and mice and of the CoQ‐dependent metabolic processes potentially affected in these pathological states. Finally, we discuss some experimental tools to dissect the various aspects of compromised CoQ oxidation.
... dependent expression profiles and nonredundant biological functions [15][16][17][18][19]. Surprisingly the double prodh1prodh2 mutant is not lethal but displays high proline content and severe sensitivity to proline treatment, disclosing the importance of a tight regulation of proline catabolism [3,18]. ...
Proline is a multifunctional amino acid that is accumulated in high concentrations in plants under various stress conditions. Proline accumulation is intimately connected to many cellular processes, such as osmotic pressure, energy status, nutrient availability, changes in redox balance, and defenses against pathogens. Proline biosynthesis and catabolism is linked to photosynthesis and mitochondrial respiration, respectively. Proline can function as a signal, modulating gene expression and certain metabolic processes. We review important findings on proline metabolism and function of the last decade, giving a more informative picture about the function of this unusual amino acid in maintaining cellular homeostasis, modulating plant development, and promoting stress acclimation.
... Mitochondrial glutamate transporters 'a bout de souffle' (BOU) and mitochondrial uncoupling proteins UCP1/2 have now been identified and it is conceivable that they could participate in the shuttling of glutamate during the proline cycle (Monné et al., 2018;Porcelli et al., 2018). ProDH, also known as proline oxidase (POX), catalyses the first and rate-limiting step of proline catabolism using FAD as a cofactor (Servet et al., 2012). In both animals and plants, ProDH is localized on the matrix side of the mitochondrial inner membrane (Elthon and Stewart, 1981;Cabassa-Hourton et al., 2016) where it transfers electrons released from proline oxidation to the mitochondrial electron transport chain. ...
The amino acid proline has been known for many years to be a component of proteins as well as an osmolyte. Many recent studies have demonstrated that proline has other roles such as regulating redox balance and energy status. In animals and plants, the well-described proline cycle is concomitantly responsible for the preferential accumulation of proline and shuttling of redox equivalents from the cytosol to mitochondria. The impact of the proline cycle goes beyond regulating proline levels. In this review, we focus on recent evidence of how the proline cycle regulates redox status in relation to other redox shuttles. We discuss how the interconversion of proline to glutamate shuttles reducing power between cellular compartments. Spatial aspects of the proline cycle in the entire plant are considered in terms of proline transport between organs with different metabolic regimes (photosynthesis versus respiration). Furthermore, we highlight the importance of this shuttle in the regulation of energy and redox power in plants, through a particularly intricate coordination notably between mitochondria and cytosol.
