Chloroplastic and mitochondrial metal homeostasis

Review

Chloroplastic and mitochondrial metal homeostasis Ce´cile Nouet, Patrick Motte and Marc Hanikenne Functional Genomics and Plant Molecular Imaging, Center for Protein Engineering, Department of Life Sciences (B22), University of Lie`ge, B-4000 Lie`ge, Belgium

Transition metal deficiency has a strong impact on the growth and survival of an organism. Indeed, transition metals, such as iron, copper, manganese and zinc, constitute essential cofactors for many key cellular functions. Both photosynthesis and respiration rely on metal cofactor-mediated electron transport chains. Chloroplasts and mitochondria are, therefore, organelles with high metal ion demand and represent essential components of the metal homeostasis network in photosynthetic cells. In this review, we describe the metal requirements of chloroplasts and mitochondria, the acclimation of their functions to metal deficiency and recent advances in our understanding of their contributions to cellular metal homeostasis, the control of the cellular redox status and the synthesis of metal cofactors.

rate and ATP production are decreased accounting for the loss of iron in respiratory complexes (mostly complexes I and II) but the capacity to oxidize NAD(P)H is maintained thanks to alternative NAD(P)H dehydrogenases [9–11]. Moreover, enhanced glycolytic and pentose phosphate pathways are suggested to sustain ATP synthesis and NAD(P)H production, respectively. This is required to support (i) the iron deficiency response, which involves both proton secretion by ATPases and NAD(P)H-dependent iron reduction by ferric chelate reductases prior cellular uptake, and (ii) the synthesis of organic acids that are important for the translocation of iron throughout the plant [2,9,12,13]. It was also shown very early on that copper deficiency strongly impacts the activity of cytochrome c oxidase, the major copper-utilizing enzyme in mitochondria [14].

Metal requirements and responses to metal deficiency Iron (Fe), copper (Cu) and manganese (Mn) exist in different ionic states and are cofactors of choice for redox reactions in cells. Redox-active metal ions can also be responsible for undesired oxidative reactions in vivo. Other metals, such as zinc (Zn), are essential structural components of proteins. Mechanisms for metal uptake, chelation, trafficking and storage have to be tightly regulated to maintain cellular metal concentrations within physiological limits (for recent reviews, see [1–4]). In photosynthetic cells, both mitochondria and chloroplasts are important components of this homeostatic network. In these compartments, high metal amounts are required for electron transport chains, redox reactions and as cofactors of many proteins (Box 1). The demand of photosynthetic organisms for these metals greatly exceeds that of nonphotosynthetic organisms [5] and metal deficiency strongly impacts both photosynthetic and respiratory functions. Leaf chlorosis (i.e. chlorophyll deficiency) is a well-known and widespread symptom of metal deficiency [6].

Chloroplasts and iron Similarly, chloroplasts have considerable metal requirements (Box 1). Up to 80% of the cellular iron in leaf cells is found in chloroplasts [15,16]. Iron starvation particularly affects photosystem I (PSI), which contains 12 iron atoms per monomer. It also causes chlorosis due to reduction in chlorophyll synthesis, possibly because the enzyme catalyzing the biosynthesis step between Mg-protoporphyrin IX monomethyl ester and protochlorophyllide requires two iron atoms [17,18]. In cyanobacteria, the abundant iron/ sulfur (Fe/S)-containing ferredoxin (Fdx) can be substituted by flavodoxin, a flavin mononucleotide-containing protein under iron deficiency [19]. In the unicellular green alga Chlamydomonas reinhardtii, a sequential remodeling of the photosynthetic apparatus occurs when cells experience a shift from iron-replete to mild and then severe iron deficiency. Mild iron deficiency first causes a disconnection of PSI and light harvesting complex I (LHCI), together with changes in the subunit composition of LHCI and size increase of the antennas of LHCII. These adaptations prevent photo-oxidative damage resulting from Fe/S cluster loss and provide a better sink for energy dissipation. Severe iron limitation ultimately results in the proteolytic degradation of LHCI subunits and both photosystems [20– 23]. In Chlamydomonas, respiration is more resistant to iron deficiency than is photosynthesis: levels of iron-containing respiratory complex subunits are maintained in mitochondria under iron deficiency, suggesting a hierarchy of iron allocation between respiratory and photosynthetic complexes in photoheterotrophic conditions [22]. It is interesting to note that the alterations of the photosynthetic

Mitochondria An analysis of the metallome of isolated Arabidopsis thaliana (Arabidopsis) mitochondria revealed a 26:8:6:1 molar ratio for iron:zinc:copper:manganese and only trace amounts of cobalt (Co) and molybdenum (Mo) [7]. A large set of metal-binding proteins has been identified in plant mitochondria [7,8] (Box 1). Under iron deficiency, mitochondria undergo drastic metabolic changes: respiration Corresponding author: Hanikenne, M. ([email protected])

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Review Box 1. Metal-dependent functions in mitochondria and chloroplasts In mitochondria, iron is notably required for respiratory complex I (NADH:ubiquinone oxidoreductase, Fe/S), respiratory complex II (succinate:ubiquinone oxidoreductase, Fe/S and heme), respiratory complex III (ubiquinol–cytochrome c oxidoreductase or bc1 complex, Fe/S and heme) and respiratory complex IV (cytochrome c oxidase, heme) as well as cytochrome c (heme), AOX (alternative oxidase, di-iron), aconitase (Fe/S), biotin synthase (Fe/S) and ferredoxins (Fe/S), whereas copper is a cofactor of complex IV. Zinc is a prosthetic group for complex IV, matrix metalloproteases and two small Tim (translocase of the inner membrane) proteins [1,16]. The first step in molybdenum cofactor (Moco) synthesis takes place in mitochondria. Moco is an essential cofactor for enzymes involved in nitrate assimilation, sulfite detoxification, abscisic acid biosynthesis and purine degradation [51]. Cobalt is also found in trace amounts in mitochondria, where it binds to several proteins. However, its function in mitochondria remains unclear [7]. In chloroplasts, iron is a component of PSII (iron) and PSI (Fe/S, iron), cytochrome b6f (Fe/S and heme) and ferredoxins (Fdx, Fe/S), whereas the electron carrier plastocyanin alone accounts for approximately 50% of the plastidial copper [1,16,31]. Manganese atoms constitute the catalytic center of the water-splitting complex in PSII [31]. Furthermore, zinc plays a role in plastidial transcription as a cofactor for the RNA polymerase and zinc fingers-containing nucleic acid-binding proteins, and as a cofactor for numerous enzymes (e.g. carbonic anhydrase, D-ribulose-5-phosphate 3-epimerase). Many proteolytic activities inside chloroplasts are zincdependent (e.g. the repair of PSII after the photodamage of the D1 protein) [16]. In both organelles, iron is also required for heme and Fe/S cluster biosynthesis and for chlorophyll synthesis in chloroplasts [17,18,94,95,124]. Metals are also cofactors of SODs that detoxify ROS in the chloroplastic nucleoid (FeSOD), stroma (FeSOD and Cu/ ZnSOD) and the mitochondrial matrix (MnSOD) [1,16].

apparatus are less pronounced when algal cells are grown in phototrophic conditions, and both photosynthesis and respiration are maintained [24], suggesting specific adaptations to lifestyle. How chloroplasts and mitochondria coordinately respond to iron deficiency in plants that are strictly phototrophic remains to be investigated. Open oceans are characterized by low nutrient availability and rapid fluctuations in light intensity during the day or with water depth. Constitutive differences in the photosynthetic architecture of oceanic cyanobacteria, diatoms and green algae have been linked to adaptation to long-term iron deficiency. These differences consist of reduced PSI and cytochrome b6f complexes, two major iron users, and a rerouting of the electron flow to oxygen directly downstream of PSII through a plastoquinol terminal oxidase, a di-iron enzyme that decreases cellular iron requirements while maintaining photosynthetic rates. This would allow sustained PSII-dependent ATP production despite low PSI abundance under iron limitation but also protects PSII at high irradiance by alleviating the redox pressure on PSII electron acceptors [25–27]. Chloroplasts and copper In plants, more than half of the copper is found in chloroplasts, mostly associated to the electron carrier plastocyanin and the Cu/Zn superoxide dismutase (SOD) [1,16]. In Chlamydomonas, the Crr1 transcription factor, a Squamosa promoter binding-like protein, controls the replacement of plastocyanin by the heme-containing cytochrome 396

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c6 under copper deficiency, which maintains electron transfer from cytochrome b6f to PSI. Crr1 also regulates genes involved in heme and chlorophyll biosynthesis to support a higher need for heme when cytochrome c6 synthesis is induced and adjust the interactions between photosystems and light harvesting complexes in response to copper status, respectively [17,28–30]. Similar to iron (see above), prioritization has also been suggested for copper that would be reallocated from chloroplastidial plastocyanin to mitochondrial cytochrome c oxidase under copper deficiency [31]. In plant chloroplasts where cytochrome c6 is absent, plastocyanin is indispensable, and it is suggested that plastocyanin has priority for copper delivery [31–36]. Moreover, one isoform of plastocyanin acts as a copper buffering system in chloroplasts under copper excess in Arabidopsis [36]. The closest homolog of Crr1 in Arabidopsis, Spl7, is also involved in the coordination of the copper deficiency response. Among other targets, it controls, via the action of microRNAs, a decrease in Cu/ZnSOD and an increase of FeSOD in chloroplasts to compensate for the loss of Cu/ZnSOD [37,38]. Chloroplasts, manganese and zinc Manganese atoms are part of the catalytic center of the water-splitting complex in PSII; therefore, manganese deficiency results in PSII photoinhibition, the loss of the D1 PSII subunit that binds the manganese cluster and the production of reactive oxygen species (ROS) [39–41]. The Arabidopsis nramp3nramp4 double mutant, which is unable to remobilize vacuolar manganese in adult leaves, contains less functional PSII but has normal levels of mitochondrial MnSOD [42] (Figure 1). In barley (Hordeum vulgare), the differential ability to grow under low manganese supply was recently linked to differences in PSII damage and state transitions under manganese deficiency [43]. Similarly, a better maintenance of the photochemical capacity has been linked to higher zinc efficiency of rice (Oryza sativa) cultivars [44]. Metal import and export The first step of metal transport into chloroplasts and mitochondria is through the outer membranes that are generally viewed as nonselective barriers (but see [45]). Thereafter, transport through the inner membranes (and the thylakoid membranes in chloroplasts) requires specific transporters (Figure 1). Mitochondria Thus far, proteins involved in metal import into plant mitochondria remain mostly unknown. Ferric chelate reductase(s), encoded by FRO genes in plants, might be involved in mitochondrial iron transport because FRO8 has been identified in the mitochondrial proteome [46]. The closest Arabidopsis homolog of the yeast Mmt1 and Mmt2 proteins, two cation diffusion facilitators involved in iron import into mitochondria [47], is MTP6 whose localization and transport specificity have not been established [48]. Changes in the MOT1 gene expression level have been linked to the natural variation of molybdenum accumulation in the shoots of several Arabidopsis accessions [49]. The localization of MOT1 remains unclear. The protein has

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Figure 1. Metal homeostasis in mitochondria and chloroplasts. Metal-requiring functions, metalloproteins, as well as putative metallochaperones and metal transporters are represented for both organelles. As vacuoles play a key role in metal homeostasis in mitochondria and chloroplasts, several vacuolar metal transporters [66,112,133– 135] are also illustrated. Proteins and processes associated with iron (Fe), copper (Cu), zinc (Zn), manganese (Mn), cobalt (Co) and molybdenum (Mo) are differentiated by colors: light blue, red, dark blue, yellow, green and gray, respectively. Transmembrane transporters are represented by boxes and arrows, together with their putative substrates. Question marks point to uncertain functions or unidentified components. Font sizes of the symbol for each metal are representative of the relative abundance of each metal in each organelle. CI to CV designate the five respiratory complexes embedded in the inner mitochondrial membrane.

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been localized to the plasma membrane and proposed to function in molybdenum cellular uptake in an initial report [50]. MOT1 has also been localized to the mitochondria, suggesting a function in molybdenum import into the organelle [49], where the first step of molybdenum cofactor (Moco) synthesis is likely to take place [51]. However, molybdenum insertion into the Moco precursor occurs in the cytosol [51]. The ABC transporter STA1/ATM3 has been involved in the export of precursors of the Fe/S cluster and/or Moco: atm3 mutants are defective in both Fe/S- and Moco-requiring cytosolic enzymes [52–54]. ATM3 and an algal homolog also play a role in heavy metal tolerance, suggesting a possible role of ATM3 and its unknown substrate in the export of metal from mitochondria [55,56]. The function of ATM1 and ATM2 that are also localized in the mitochondria remains unclear [52]. Chloroplasts and iron In chloroplasts, not all components of metal import have been identified yet but important progress has been made in recent years. Ferric iron uptake through the plasma membrane is mostly mediated by Fut (ferric iron uptake) ABC transporters in cyanobacteria [5,57]. It is not known whether a similar system exists in plants (Figure 2). However, the NAP14 nonintrinsic ABC protein (NAP), which is the closest homolog of the Fut system in Arabidopsis, is plastid-localized and a nap14 Arabidopsis mutant accumulates an excess of iron. NAP14 could either be part of an iron transport complex or be a plastid regulator of iron homeostasis in plants [58]. Similar to other plastidial NAPs, it could also be involved in Fe/S cluster biogenesis

CtaA/PAA1

[59]. In chloroplasts, active ferrous iron transport through the inner membrane has been measured by biochemical methods [60]. This is consistent with the recent report showing that iron reduction by FRO7 is required for iron uptake into chloroplasts [61]. PIC1, a cyanobacterial permease-like protein, might be a chloroplastidial iron importer. It is capable of iron and copper transport in yeast and a pic1 Arabidopsis mutant displays phenotypes that are consistent with a defect in iron transport [62]. However, it has also been identified as a component of a protein translocation complex [63] and the role of PIC1 in iron transport in plants remains to be demonstrated (Box 2). The MAR1 chloroplastidial protein has also been implied in iron homeostasis in Arabidopsis. A mar1 mutant was first identified as resistant to multiple antibiotics, but it also displays a chlorotic phenotype that can be rescued by exogenous iron [64]. MAR1 is a close homolog of the ferroportin 1 and 2 proteins (FPN1 and FPN2, also called IREG1 and IREG2) that are involved in metal (iron, cobalt) vascular loading and the vacuolar buffering of metal excess during the iron deficiency response, respectively [65,66]. It has been proposed that MAR1 transports an iron chelator that is mimicked specifically by aminoglycoside antibiotics [64]. Chloroplasts and copper The PAA1 and PAA2 P-type ATPases are responsible for copper transport across the inner and thylakoid membranes, respectively. Consistently, a paa1 mutant is defective both in stromal Cu/ZnSOD and in plastocyanin, whereas the paa2 mutant only lacks plastocyanin. A paa1-

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Figure 2. Comparison of metal homeostasis in cyanobacteria and chloroplasts. Chloroplasts and mitochondria have an endosymbiotic origin stemming from the engulfment of a cyanobacterium and an a-proteobacterium, respectively, by a ‘primitive’ eukaryote. These past events must have at least partially determined the metal homeostasis mechanisms in present day photosynthetic organisms. To illustrate this point, the figure compares metal homeostasis in modern cyanobacteria and chloroplasts, revealing commonalities and differences in metal transporters and metalloproteins. Ferric iron uptake through the plasma membrane is mostly mediated by FutABC transporters in cyanobacteria [57]. In Arabidopsis, the closest homolog of Fut is NAP14, which has a function in iron homeostasis [58]. The Arabidopsis PIC1 protein, which is possibly involved in iron transport, displays homology with cyanobacterial permease-like proteins [62]. Whether the cyanobacterial proteins are metal transporters has not been determined. For copper uptake into chloroplasts, the homologs of the cyanobacterial CtaA and PacS proteins are PAA1 and PAA2, respectively [34,68]. In cyanobacteria, the chaperone ATX1 delivers copper from CtaA to PacS, whereas no plant ATX1 homolog has been identified in chloroplasts [87,89]. Cyanobacterial ABC transporters involved in manganese and zinc uptake (MntABC and ZnuABC, respectively [5,73]) have no identified counterparts in chloroplasts. Finally, several essential metalloproteins are well conserved from cyanobacteria to higher plant chloroplasts: FeSOD, SUF machinery of Fe/S cluster biogenesis, ferritin and plastocyanin. By contrast, only a few mitochondrial proteins can be traced back to an a-proteobacterial ancestor. Indeed, low sequence similarity between bacterial and eukaryotic proteins prevents the detection of either homology or a strong signal in phylogenetic analyses [136]. A detailed comparison of human and yeast mitochondrial proteomes with aproteobacteria proteomes suggests that most ion transport proteins found in mitochondria evolved from non- (or possibly undetectable) a-proteobacteria proteins [137]. Nevertheless, together with earlier observations [94], this study confirmed that the ISC machinery of Fe/S cluster biogenesis is conserved (not represented). In the figure, transmembrane transporters are represented by boxes and arrows. Transporters and metalloproteins associated with iron (Fe), copper (Cu), zinc (Zn) and manganese (Mn) are differentiated by colors: light blue, red, dark blue and yellow, respectively. Question marks highlight the unidentified putative homologs. The envelope (Env) and plasma membrane (PM) of cyanobacteria correspond to the outer (OM) and inner membranes (IM) of chloroplasts, respectively.

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Box 2. Metals and protein translocation into organelles Recent reports have started to shed light on a link between metals and protein import into both mitochondria and chloroplasts. It has been revealed in yeast that cytosolic zinc could act as a chemical chaperone for small mitochondrial Tim proteins [85]. Indeed, in the cytosol small Tim proteins can be oxidized, which prevents their import into mitochondria. By stabilizing thiols, zinc protects the reduced proteins from this oxidative folding in the cytosol and maintains the small Tim proteins in an import-competent form. Because (i) the import of the zinc-bound form is inefficient and (ii) zinc inhibits the Mia40–Erv1 pathway, which is involved in the oxidative folding of imported proteins in the intermembrane space, it is suggested that zinc is then released upon the import of the protein in the apoform. Zinc binding to the small Tim proteins is thereby highly dynamic. How the equilibrium between the apo- and zinc-bound forms is controlled in the cytosol remains unknown [85]. Zinc might have a similar function in plant mitochondria [138], although a recent study demonstrated that unlike in yeast the Arabidopsis Mia40–Erv1 machinery does not play a role in the import and assembly of small Tim proteins [139]. In chloroplasts, defects in protein import affect the whole plant iron homeostasis. Initially described as a component of a chloroplastidial protein translocation complex [63], PIC1 has recently been suggested to act as an iron importer into chloroplasts in Arabidopsis (see main

paa2 double mutant is seedling lethal, highlighting the crucial role of copper in chloroplasts [34,67]. This uptake system is functionally conserved from cyanobacteria to higher plants [5,34,68] (Figure 2). Another P-type ATPase HMA1 might also be involved in chloroplastidial copper import. HMA1 transports both zinc and copper in yeast and localizes to the chloroplast envelope. A hma1 mutant accumulates less copper in plastids, displays reduced SOD activity, but a normal plastocyanin level, and has a defect in the photosynthetic water–water cycle, an alternative pathway to dissipate electrons [69–71]. However, a more recent study suggested that HMA1 is involved in zinc export from the chloroplast, based on zinc hypersensitivity and increased zinc accumulation in the chloroplast of the mutant [72], questioning the initial report involving HMA1 in chloroplastic copper import. Chloroplasts, manganese and zinc In cyanobacteria, a system for zinc uptake called ZnuABC [73] and a similar high affinity manganese uptake system (MntABC) [5] are induced under deficiency. Such systems have not been identified in plant chloroplasts, and the uptake mechanisms for zinc and manganese in these organelles remain unknown (Figure 2). Metal chaperones So-called metallochaperones are shuttle proteins that ensure proper metal delivery to target apoproteins and also prevent metal toxicity by contributing to maintain virtually no free metal ions in cells [74]. Only a few chaperones have been identified thus far in plant mitochondria and chloroplasts. Mitochondria The role of chaperones in copper delivery for the mitochondrial cytochrome c oxidase assembly has been well characterized in yeast, where 11 proteins, as well as a matrix copper pool bound to an unknown ligand, are required (reviewed in [75,76]). In photosynthetic organisms, several

text and [62]). Moreover, a mutation disabling the induction of ferric chelate reductase activity (FRO2) in Arabidopsis roots under iron deficiency affects a gene encoding the chloroplastidial protein cpFtsY [140]. This protein is part of the cpSRP (chloroplast signal recognition particle) pathway responsible for protein insertion into thylakoid membranes in chloroplasts. The roots seem to respond appropriately to the systemic iron-deficiency signal in the mutant, and the authors suggest that the mutation might affect the post-transcriptional control of FRO2 [140]. Further work is needed to untangle the complex relation between the induction of ferric chelate reductase activity and protein translocation into chloroplasts. Finally, a mutation in ClpC1, a gene encoding a stromal protease that is required for importing proteins into chloroplasts, results in a chlorotic phenotype that is rescued by iron supplementation in Arabidopsis. The mutation is also responsible for the deregulation of FRO8, NRAMP3 and NRAMP4 gene expression [141], indicating an interaction between iron homeostasis in chloroplasts and mitochondria and vacuoles, respectively. It is worth noting that the upregulation of ClpC1 was observed in a mutant defective for cpSRP54, another component of the cpSRP transport pathway, further suggesting a link between iron homeostasis and several actors involved in protein import into chloroplasts [142].

homologs (COX17, COX11, SCO1 and COX19) of these chaperones have been identified that play a similar function in mitochondria, and might also be involved in metal detoxification and protection against oxidative stress [77– 80]. A putative chaperone homologous to the yeast Mtm1 protein involved in manganese delivery to mitochondrial MnSOD has been characterized in Arabidopsis [81]. Although it has been proposed that no chaperones are required to deliver zinc to appropriate apoproteins based on zinc affinity for protein metal-binding sites [82,83], a yet to be identified cationic zinc component constitutes a labile zinc pool in the yeast mitochondrial matrix, which could either act as a detoxification mechanism or as a metal reservoir for the metallation of zinc-binding proteins in the matrix. The Mzm1 protein not only controls this matrix zinc pool but is also involved in the proper stability of respiratory complex III [84]. It remains to be determined whether a ligand-bound labile zinc pool exists in plant mitochondria. Interestingly, it was recently suggested that zinc itself could act as a chemical chaperone for protein import into mitochondria [85], which revealed a possible interaction between protein translocation into organelles and metal homeostasis (Box 2). Chloroplasts In chloroplasts, copper has to be delivered to two main targets: plastocyanin and Cu/ZnSOD [1,16,34]. Apo- and holoproteins have a similar structure; therefore, plastocyanin could spontaneously acquire copper in the thylakoid lumen after import by PAA2 [1,86] (Figure 1). In cyanobacteria, an ATX1-like protein delivers copper to a PAA2 homolog [87] (Figure 2). In plants, two cytosolic ATX1-like proteins have been involved in copper delivery to P-type ATPases, but no homolog has been localized to chloroplasts or described to interact with PAA1 or PAA2 [88,89]. However, a copper chaperone for SOD (CCS) that is localized in both cytosolic and plastidial compartments has been identified in Arabidopsis. CCS is responsible for copper delivery 399

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and the activation of cytosolic, peroxisomal and chloroplastidial Cu/ZnSODs [90–92]. Finally, a cytosolic chaperone involved in iron delivery to ferritin has been identified in humans [93]. In plants, ferritins accumulate in both mitochondria and chloroplasts (see oxidative stress section below). How iron is delivered to these proteins remains unknown. Likewise, only a few chaperones involved in the transfer of heme or Fe/S clusters to apoproteins have been characterized thus far (see below) [94,95]. Recently, putative ubiquist zinc chaperones have been identified that might play a role in zinc homeostasis in both organelles [96]. Oxidative stress and the control of the cellular redox status In both chloroplasts and mitochondria, the electron transport chains that rely on the use of metals and oxygen are a source of ROS. Mechanisms have evolved to protect these machineries from metal toxicity and oxidative damage [97,98]. Different antioxidant enzymatic and nonenzymatic systems are present in both organelles (Figures 1 and 3). When the redox control capacity of chloroplasts is reduced, it results in metal hypersensitivity [99,100]. Chloroplasts play a role in the biosynthesis of glutathione (GSH), which is the most abundant low molecular weight

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thiol in the cellular redox system. GSH is crucial for ROS detoxification as well as sensing the cellular redox status and transmitting these redox changes to target proteins [101]. GSH also contributes to metal tolerance through the reduction of metal-mediated ROS, direct metal binding or as a precursor to phytochelatin biosynthesis [102]. In Arabidopsis, GSH is synthesized by two enzymes, g-glutamylcysteine synthetase and glutathione synthetase, which are localized in chloroplasts and both chloroplasts and the cytosol, respectively [103]. Three plastid chloroquine resistance-like transporters (CLT1–3) are responsible for GSH transport from plastids to the cytosol (Figure 3) and, therefore, play important roles in regulating GSH levels and redox status in the cytosol [100]. Similar to other mutants defective in GSH metabolism, a triple clt mutant is hypersensitive to cadmium [100,102,104], highlighting the contribution of chloroplasts to the handling of metalinduced oxidative damage in cells. Ferritin is a multimeric protein that can store up to 4500 ferric iron (Fe3+) atoms. In animal cells, ferritin expression is increased upon iron excess, and ferritin is the main iron storage system in the cytosol, whereas it provides protection against iron toxicity and oxidative damage in mitochondria [105–108]. In photosynthetic cells, ferritins are found in chloroplasts and mitochondria. Recent studies in

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Figure 3. Coping with oxidative stress in chloroplasts. The chloroplast as an O2-producing compartment is facing the production of ROS and has evolved nonenzymatic and enzymatic systems for ROS detoxification. Nonenzymatic components include ferritin, glutathione (GSH: reduced form; GSSG: oxidized form), ascorbate (and its oxidized form monodehydroascorbate that disproportionates into dehydroascorbate), a-tocopherols and carotenoids. SODs, glutathione reductase (GR) and peroxidase, ascorbate peroxidase, monodehydroascorbate reductase (MDHAR) and dehydroascorbate reductase (DHAR) constitute enzymatic systems. GR, MDHAR and DHAR allow the so-called ascorbate–GSH cycle, which has a pivotal role in defense against ROS-induced oxidative damage [97,98]. Additionally, the chloroplast is the site of g-glutamylcysteine and GSH synthesis by g-glutamylcysteine synthetase and glutathione synthetase, respectively, which are exported by CLT transporters into the cytosol where GSH plays an important role in the control of the cellular redox status [100,101].

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Review both Chlamydomonas and Arabidopsis have revealed that, in these species, ferritin does not constitute a major iron pool, but is involved in the protection against oxidative stress. Hence, in Chlamydomonas, the FER1 and FER2 genes encoding ferritins are induced by iron deficiency, and a fer1 mutant is more sensitive to oxidative stress under photoheterotrophic conditions. This suggests that ferritin is needed in chloroplasts to buffer iron that is released following the degradation of PSI and Fdx in iron-limited cells and to redistribute iron to newly synthesized proteins [109,110]. In Arabidopsis, the FER1, FER3 and FER4 genes are expressed in leaves, whereas FER2 is expressed in seeds. All four ferritins protect leaves and seeds, respectively, from free iron-mediated oxidative stress by buffering iron [111]. In Arabidopsis seeds, only 5% of iron is ferritin-bound and the main iron storage compartment is the vacuole where vacuolar transporters for iron uptake (VIT1) or remobilization (NRAMP3 and NRAMP4) play a key role in proper seedling germination [42,111–113] (Figure 1). However, interactions between the vacuole and plastid in iron homeostasis and oxidative stress are also crucial [114]. It is interesting to note that in other species such as pea (Pisum sativum) or soybean (Glycine max), approximately 90% of total iron in the seeds is associated to ferritin [108]. Another example is oceanic diatoms using ferritin to store iron that is later used for blooms [115]. This highlights differences between species in iron storage management. Ferritin is also localized in mitochondria. A fer4 Arabidopsis mutant displays different rearrangements of the respiratory machinery but is not impaired in its development or response to abiotic stress [116,117]. Furthermore, the mitochondrial protein frataxin has been proposed to play essential roles in cellular respiration, iron homeostasis, Fe/S cluster biogenesis, heme biogenesis and protection against oxidative stress [118]. The protein is highly conserved from bacteria to plants and mammals, suggesting conserved functions. A frataxin homolog has been characterized in Arabidopsis: a knockout is embryo lethal, whereas the analysis of knockdown plants has indicated that plant frataxin is required for mitochondrial Fe/S protein biogenesis and protection against oxidative stress [119,120]. Recent work has revealed the relation among mitochondrial frataxin, cytosolic nitric oxide (NO) and iron homeostasis [121]. NO is proposed to constitute a signaling molecule in the iron deficiency response via a crosstalk among hormones, NO, iron and GSH (see [122] for an extensive review). A frataxin-deficient mutant displays elevated iron and NO levels. This high NO content is responsible for the induction of both FER1 and FER4 gene expression and protects against increased ROS production [121,122]. Similar to animals, frataxin also plays a role in heme biogenesis in plants [118,123]. Heme and Fe/S cluster biogenesis Heme and Fe/S clusters are two iron-containing cofactors that are involved in various processes, including respiration and photosynthesis, as well as many extraorganellar functions [94,95]. In plants, the tetrapyrrole biosynthetic pathway takes place in chloroplasts. Heme is synthesized from protoporphyrinogen IX, an intermediary of this path-

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way, in chloroplasts and possibly in mitochondria. How heme is transported between compartments and the contribution of each organelle to cytosolic heme requirements remain unclear (reviewed in detail in [95]). In fungi or mammals, Fe/S cluster assembly takes place in mitochondria only, whereas photosynthetic organisms possess an additional machinery in chloroplasts. Fe/S cluster assembly is complex and involves the mobilization of elemental sulfur from cysteine, the acquisition of iron, the assembly of iron and sulfur and finally the insertion of the Fe/S cluster into apoproteins. Cysteine desulfurase, scaffold proteins, chaperones and transporters are required for this process. These factors were first identified in bacteria that host three machineries: ISC (iron–sulfur cluster), SUF (sulfur fixation) and NIF (nitrogenase fixation) (see [94,124] for recent and detailed reviews). In plants, these systems coexist but originate from different endosymbionts: ISC-like machinery is present in mitochondria, whereas SUF components are present in plastids. It is hypothesized that SUF machinery has a lower sensitivity to oxidative stress than does ISC machinery and, therefore, was retained from cyanobacteria to allow the synthesis of Fe/S clusters in oxygen-producing chloroplasts [125]. Plants also possess members of the NIF system in plastids (NFU1–3 A. thaliana) and mitochondria (NFU4–5) [126]. Two distinct assembly pathways might, therefore, exist in plastids because an nfu2 mutation only affects a subset of plastid Fe/S proteins [127]. Interesting and yet unsolved questions are how the two organelles interact with each other and with the cytosol to properly deliver Fe/S clusters to target proteins and how iron and cysteine are shared to support the synthesis of the clusters. It was recently shown that SufE1, a cysteine desulfurase activator, is localized in both mitochondria and chloroplasts in Arabidopsis. A sufE1 mutant is lethal and can only be rescued if SufE1 is expressed in both organelles, demonstrating that plastidial and mitochondrial Fe/S cluster biogenesis share a common essential component [128]. The analysis of the atm3 Arabidopsis mutant (see above) revealed the crucial role of mitochondria in the assembly of cytosolic Fe/S proteins [53]. Concluding remarks Chloroplasts and mitochondria have important metal requirements and, therefore, they have evolved mechanisms to prioritize metal targets under metal deficiency. The uptake systems for many metals in mitochondria and chloroplasts remain to be identified. The organelles also contribute to cellular metal homeostasis, the control of the cellular redox status and the synthesis of metal cofactors. Recent studies have started to shed light on the interactions among the metal homeostasis of chloroplasts, mitochondria and vacuoles [42,114,129]. A role for ROS and NO in the signaling between organelles and the cytosol is also emerging [130,131]. How metals compete for uptake is also a question of interest [132]. New avenues of investigations should aim to further reveal the interactions between metal homeostasis in chloroplasts and mitochondria, how the metal status is sensed in the organelles and how it is signaled to other compartments to adapt metal uptake and trafficking in the cell. 401

Review Acknowledgments The authors thank Dr. P. Cardol for the critical reading of the manuscript. Research in the author’s laboratory is supported by the ‘Fonds de la Recherche Scientifique – FNRS’ (FNRS; grant nos. 2.4638.05, 2.4540.06, 2.4583.08 and 2.4581.10) and the ‘Fonds Spe´ciaux du Conseil de la Recherche’ from the University of Lie`ge. C.N. and M.H. are postdoctoral researcher and research associate of the FNRS, respectively.

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