TY - JOUR
AU - Nishizawa, Naoko K
AB - Abstract Improvement of crop production in response to rapidly changing environmental conditions is a serious challenge facing plant breeders and biotechnologists. Iron (Fe), zinc (Zn), manganese (Mn), and copper (Cu) are essential micronutrients for plant growth and reproduction. These minerals are critical to several cellular processes including metabolism, photosynthesis, and cellular respiration. Regulating the uptake and distribution of these minerals could significantly improve plant growth and development, ultimately leading to increased crop production. Plant growth is limited by mineral deficiency, but on the other hand, excess Fe, Mn, Cu, and Zn can be toxic to plants; therefore, their uptake and distribution must be strictly regulated. Moreover, the distribution of these metals among subcellular organelles is extremely important for maintaining optimal cellular metabolism. Understanding the mechanisms controlling subcellular metal distribution and availability would enable development of crop plants that are better adapted to challenging and rapidly changing environmental conditions. Here, we describe advances in understanding of subcellular metal homeostasis, with a particular emphasis on cellular Fe homeostasis in Arabidopsis and rice, and discuss strategies for regulating cellular metabolism to improve plant production. Chloroplast, copper, iron, manganese, mineral transport, mitochondria, zinc Introduction Plants require carbon dioxide, water, oxygen, sunlight, and minerals for optimal growth. Due to the rapidly changing environment, ensuring food security for an increasing world population remains a challenge for plant scientists. Among minerals, metallic micronutrients such as iron (Fe), copper (Cu), manganese (Mn), and zinc (Zn) are essential for all higher organisms, and regulation of their uptake, storage and distribution is indispensable to plant growth and development (Marschner, 1995). Fe, Cu, and Mn readily change their oxidative state, which enables these transition metals to participate in vital cellular processes such as photosynthesis, the electron transport chain, and DNA replication. On the other hand, these changes can affect plant growth through the production of reactive oxygen species (ROS). Fe is essential to cellular respiration as well as chlorophyll development and function, photosynthetic electron transport and several other metabolic processes (Grotz and Guerinot, 2006). It is particularly important for the functional regulation of chloroplasts and mitochondria and its deficiency can be identified based on interveinal chlorosis. It is integral to photosynthesis, as a component of photosystem I (PSI), photosystem II (PSII), and cytochrome b6f. Fe is also important for the functions of ferredoxin, Fe-requiring enzymes, frataxin, twin arginine translocase, heme proteins, Rieske [2Fe–2S] protein, and other Fe–S cluster proteins and secretion systems. Cu serves as a cofactor for enzymes involved in integral cellular processes such as photosynthesis and respiration, and is toxic when accumulated in excess. A notable example of a protein that requires Cu to perform its function in the chloroplast is plastocyanin, a small soluble Cu protein in the thylakoid that mediates electron transfer to PSI. Cu chaperones such as PCH1 are also important for chloroplast function, while ROS-detoxifying Cu/Zn-superoxide dismutase (Cu/Zn-SOD) employs Cu2+/Cu+ as its redox-active cofactor (Schmidt et al., 2020). In mitochondria, Cu is essential for energy production and ROS detoxification, e.g. Cu is integral to cytochrome c oxidase assembly. It also serves as a signaling molecule that links mitochondria with other cellular compartments, e.g. via the mitochondrial Cu chaperone COX19, which has been suggested to participate in regulation of Cu and Fe homeostasis in plants (Garcia et al., 2014, 2019). Mn serves as a cofactor or activator of several important proteins, including Mn-superoxide dismutase, oxalate oxidase, RNA polymerase, malic enzyme, isocitrate dehydrogenase, and phosphoenolpyruvate carboxykinase (Marschner, 1995; Socha and Guerinot, 2014). In the chloroplast, Mn is essential for the photosynthetic electron transport chain and generation of ATP. It is indispensable for photosynthesis, as PSII employs Mn for the splitting of water (Kok et al., 1970; Marschner, 1995; Schmidt et al., 2020). Mn is also a component of PsbP and Mn-requiring enzymes in the chloroplast. PSII activity is particularly sensitive to Mn deficiency (Schmidt et al., 2016, 2020). Mn transport to vacuoles and the Golgi apparatus is critical to several physiological processes, including plant fertility and root development (Ma et al., 2018; Tsunemitsu et al., 2018). In contrast to Fe, Cu, and Mn, Zn does not readily change redox states and plays an integral role in nucleic acid, carbohydrate, protein, and lipid metabolism (Bashir et al., 2012; Clemens, 2017; Ishimaru et al., 2011a; Suzuki et al., 2012). It is critical for the function of DNA-binding Zn-finger motifs, RING-finger and LIM domains, RNA polymerases, reverse transcriptases, and transcription factors (Marschner, 2011). It is required for various chloroplast functions; for example, Cu/Zn-SOD is involved in the dismutation of superoxide to hydrogen peroxide, while mitochondrial Zn is required for the protein import apparatus used for both carrier protein transport to the inner membrane and degradation of target peptides (Lister et al., 2002; Moberg et al., 2003; Tan et al., 2010). Hence, Fe, Cu, Mn, and Zn play critical roles in maintaining cellular processes in subcellular organelles such as the mitochondria, chloroplast, and the endomembrane system. Changes in the availability of these minerals significantly affect plant growth and development (Bashir et al., 2013a, 2014, 2016; Vigani et al., 2016, 2019; Schmidt et al., 2020). The availability of these metals is significantly compromised under severe soil conditions such as alkaline soils, which represent around 30% of the world’s arable land. Similarly, Fe toxicity is often observed in acidic soils (Fageria et al., 2008, 2011). Mn availability is a problem in alkaline soils, and Mn toxicity is observed in acidic soil (Rengel, 2015). Zn is low in certain soils, such as leached acidic soils in tropical climates, and may be unavailable to plants where soil chemistry favors the formation of Zn complexes with low solubility (Rengel, 2015). Deficiency or excess of one metal also affects the uptake and utilization of other metals; the main reasons for the former and latter effects are considered to be competition and mismetalation, respectively. Mismetalation occurs when one element is in short supply or is out-competed for binding, and may significantly affect cell and protein functions (Schilter, 2019). The uptake and distribution of metals are also affected by other stresses, such as drought and biotic stresses (Rasheed et al., 2016). Here, we review the recent developments in elucidating the distribution of minerals to various subcellular organelles, with a particular emphasis on the cellular Fe distribution in Arabidopsis and rice, and discuss strategies for crop improvement via regulating the distribution of these metals. Cellular metal homeostasis is integral to plant growth and development Roots acquire minerals from the rhizosphere. While utilizing these minerals for their own essential metabolic processes, roots serve as a tunnel to transport the minerals to aerial parts through the xylem and phloem. Notably, these minerals are ultimately utilized at the cellular level and their distribution to the cytoplasm and other subcellular compartments, such as the nucleus, chloroplasts, and mitochondria, is a prerequisite for optimal metabolism. These subcellular organelles require minerals for specific metabolic processes, while vacuoles serve as reservoirs for regulating cellular metallic balance. Membrane proteins known as transporters play a critical role in regulating cellular metal transport. Several families of transporters maintain the distribution of metals to ensure cellular metal homeostasis (Vigani et al., 2013a, 2019; Socha and Guerinot, 2014; Finazzi et al., 2015; López-Millán et al., 2016; Kato et al., 2019). Plants synthesize and utilize several chelating agents, such as citrate, malate, ascorbate, phenolics, nicotianamine (NA) and mugineic acids (MAs) to solubilize metals. These chelators mitigate the production of ROS and avoid the oxidative damage that can be caused by free metals (Jeong and Guerinot, 2009; Palmer and Guerinot, 2009; Bashir et al., 2011b, 2017; Ishimaru et al., 2011b; Grillet et al., 2014). In general, the redox state of cellular compartments, concentration of metal chelators, and availability of metals at a particular ratio are critical for optimal plant growth. The roles of only a small number of intracellular metal transporters have been elucidated to date. Further efforts should be dedicated to clarifying the regulation of metal transporters that transport essential micronutrients to subcellular organelles, with a particular emphasis on the mitochondrion and chloroplast. Regulating the expression of these transporters could serve as a critical tool for improving crop production. Vacuoles play a central role in supporting optimal cellular metabolism through efficient metal accumulation and distribution A vacuole is a single membrane-bound organelle occupying a major area inside the plant cell. Vacuoles are thought to be metabolically inactive, but play a central role in cellular metabolism by regulating the distribution of toxic metabolites and metals. In plants, the number of characterized transporters localized to vacuoles is much greater than that of any other organelle, such as the chloroplast or mitochondrion (Bashir et al., 2016, 2019a). Excess metals are deposited in vacuoles to avoid metal toxicity and then released when needed (Fig. 1). Whether Fe and other metals are stored in the free ionic form or are bound to metal ligands inside the vacuole remains unclear (Vigani et al., 2019). Metal speciation may depend on plant growth stage, as mineral ratios can differ significantly between vegetative and seed development stages. In seedlings, Fe may be co-localized with phosphorus, whereas at the seed development stage, Fe and Mn may be bound to phytate (Hirsch et al., 2006; Bruch et al., 2015). Fe is thought to be predominantly stored in the ferric (Fe3+) form in vacuoles (Vigani et al., 2019), and therefore its reduction might be required prior to its export to the cytoplasm. Rice ferric reductase oxidase 1 (OsFRO1) is localized to the vacuolar membrane in rice protoplasts (Li et al., 2019). OsFRO1 is primarily expressed in leaves and its expression is down-regulated under excess Fe conditions. OsFRO1 overexpressing (OX) plants exhibit sensitivity to Fe toxicity, while knockdown plants are tolerant of excess Fe. OsFRO1 appears to reduce ferric Fe into Fe2+ in the vacuole as part of the Fe export mechanism to the cytoplasm. Similar mechanisms can be reasonably expected to exist in other plant species. Moreover, ascorbate and other metal ligands such as NA, MAs, and coumarins might also contribute to metal storage in vacuoles (Haydon et al., 2012; Rajniak et al., 2018; Che et al., 2019; Vigani et al., 2019). Efflux of NA 1 (ENA1) is a member of the major facilitator superfamily (MFS) that is localized to the plasma membrane and vesicles in rice (Nozoye et al., 2011; Nozoye et al., 2019). The ENA1 homologs Zn-induced facilitator 1 (ZIF1) and ZIF2 have been suggested to transport free NA from the cytosol into vacuoles (Haydon and Cobbett, 2007; Haydon et al., 2012; Remy et al., 2014). Moreover, a rice vacuolar MA transporter (OsVMT) sequesters 2′-deoxymugineic acid (DMA) into the vacuole (Che et al., 2019). OsVMT knockout plants accumulate significantly increased levels of Fe and Zn in polished rice grains, suggesting that enhanced availability of DMA increases solubilization of Fe and Zn deposited at the node. These reports demonstrate that metal chelators are of extreme importance due to their regulation of vacuolar metal storage. Fig. 1. Open in new tabDownload slide Summary of metal transport in the vacuole: proteins involved in micronutrient mineral transport into or out of the vacuole. All proteins in the figure are from Arabidopsis except as noted with the prefix Os (Oryza sativa L.; rice) Fig. 1. Open in new tabDownload slide Summary of metal transport in the vacuole: proteins involved in micronutrient mineral transport into or out of the vacuole. All proteins in the figure are from Arabidopsis except as noted with the prefix Os (Oryza sativa L.; rice) Several transporters have been characterized that regulate metal influx and efflux from vacuoles. In Arabidopsis, FPN2 (IREG2) participates in Fe sequestration into vacuoles (Schaaf et al., 2006). Vacuolar Fe transporter 1 (VIT1) has been characterized in great detail. VIT1 deposits Fe and Mn in the vacuole, and also plays a critical role in Fe accumulation and distribution in seeds (Kim et al., 2006; Schaaf et al., 2006; Morrissey et al., 2009; Chu et al., 2017). Change in the expression of VIT1 significantly alters Fe localization in Arabidopsis seeds (Kim et al., 2006). Revelation of the crystal structure of VIT1 would significantly advance our understanding of metal transport in plants and support development of genetically modified crops that preferentially transport a specific metal while avoiding others (Kato et al., 2019). VIT1 forms a dimer containing five membrane-spanning domains, among which the second transmembrane helix protrudes from the lipid membrane by about 40 Å to connect with a triangular cytoplasmic domain. This domain binds to the substrate metal ions to maintain their solubility and thereby facilitate their transport. These mechanistic insights provide significant opportunities for the improvement of crop plants (Kato et al., 2019). In rice, VIT1 and VIT2 contribute to Fe, Mn, and Zn sequestration to the vacuole, and vit1 and vit2 mutants accumulate high levels of metals in rice seeds (Zhang et al., 2012). VIT proteins are required for various physiological functions, and change in VIT expression can affect petal colors in flowers due to changes in the accumulation of pigments that form complexes with metals (Momonoi et al., 2009; Yoshida and Negishi, 2013). In addition to VIT transporters, several VIT1-like (VTL) proteins have been identified and characterized in plants (Gollhofer et al., 2014). In Arabidopsis, VTL1, VTL2, and VTL5 transport cytoplasmic Fe into the vacuole, contributing to in planta regulation of Fe homeostasis (Gollhofer et al., 2014). VTL transporters have also been identified and characterized in other crop species, although questions remain about the substrate specificity and physiological roles of these transporters. Few proteins involved in sequestering Zn to the vacuole have been identified in plants. In Arabidopsis, metal tolerant protein 1 (MTP1) and MTP3 play critical roles in sequestering excess Zn into the vacuole (Desbrosses-Fonrouge et al., 2005; Arrivault et al., 2006). Vacuolar Zn deposition is also mediated by heavy metal ATPase 3 (HMA3), which also sequesters Cd (Morel et al., 2009). The Arabidopsis cation exchanger family transporters CAX2, CAX4, and CAX5 localize to the vacuole. Of these, CAX2 transports Fe, Cd, and Mn; CAX4 transports Mn and Cd; and CAX5 appears to specifically transport Mn into the vacuole (Socha and Guerinot, 2014). VIT1 also contributes to Mn sequestration to the vacuole. Arabidopsis MTP8, MTP9, MTP10, and MTP11 complement the Mn-hypersensitive yeast mutant Δpmr1 (Chu et al., 2017). MTP8 is a functional vacuolar Mn transporter, and its expression is strongly induced by Mn excess and Fe deficiency. It protects plant cells from Mn toxicity under both excess Mn and Fe deficiency stresses (Eroglu et al., 2016). Plants defective in MTP8 (mtp8) are particularly sensitive to Fe deficiency in the presence of Mn, which is attributed to decreased ferric chelate reductase activity (Eroglu et al., 2016). Synchrotron X-ray fluorescence (SXRF) analyses of mtp8–2 mutants revealed that the Mn distribution pattern in their seeds is significantly altered. In this mutant, Mn accumulates in combination with Fe in cells surrounding the vasculature, a pattern previously shown to be driven by the vacuolar transporter VIT1 with the tradeoff of lower accumulation in hypocotyl cortex cells and sub-epidermal cells of the embryonic cotyledons (Chu et al., 2017). These results indicate that MTP8 is important for Mn distribution in seeds. Plants generally accumulate more metals in root tissues relative to aerial parts, but rice accumulates higher levels of Mn in shoot tissues than in its roots, without showing any growth defect (Ishimaru et al., 2012). Although it remains unclear why rice accumulates such a high concentration of Mn in its shoots, some mechanisms governing Mn tolerance have been reported. OsMTP8.1 and OsMTP8.2 sequester excess Mn in the vacuole and thereby contribute to Mn tolerance (Chen et al., 2013; Takemoto et al., 2017). OsVIT1 and OsVIT2 may also contribute to sequestration of Mn in the vacuole (Zhang et al., 2012). In rice, OsHMA4 sequesters Cu in root vacuoles, limiting Cu accumulation in the grain. Thus, OsHMA4 loss-of-function mutants deliver more Cu+ to the shoots and grains. A single amino acid substitution has been suggested to be responsible for the differences in grain Cu accumulation among natural variants. This natural allelic variation of OsHMA4 could be exploited to develop rice varieties with varying grain Cu concentrations (Huang et al., 2016). In plants, few transporters have been characterized to date that efflux metals from the vacuole. Arabidopsis Cu transporter 5 (COPT5) pumps out vacuolar Cu into the cytoplasm, and disruption of COPT5 affects photosynthetic electron transport, indicating that vacuolar Cu export contributes to photosynthesis (Garcia-Molina et al., 2011; Klaumann et al., 2011). Natural resistance associated macrophage proteins (NRAMPs) are integral membrane proteins regulating Mn, Fe, and Cd transport. In Arabidopsis, NRAMP3 and NRAMP4 play critical roles in mobilizing Fe, Mn, and Cd from vacuoles to the cytoplasm. YSL4 and YSL6 are members of the yellow stripe-like family in Arabidopsis and contribute to remobilization of vacuolar Fe (Conte et al., 2013), while another report found that these transporters are involved in chloroplastic metal homeostasis (Divol et al., 2013). The role of Arabidopsis NRAMP3 and NRAMP4 in releasing vacuolar Fe under limited-Fe conditions or when demand increases has been extensively documented (Lanquar et al., 2005; Mary et al., 2015; Pottier et al., 2015; Bastow et al., 2018). An nramp3/nramp4 double mutant failed to mobilize Fe stored in seeds and required external supply of Fe for development. Interestingly, failure to mobilize seed Fe during germination strongly affects plastids, but not mitochondria (Bastow et al., 2018). ZIP1 also contributes to remobilization of vacuolar Mn and Zn in Arabidopsis (Milner et al., 2013). Arabidopsis VIT1 and NRAMP3/NRAMP4 transport Fe in opposite directions. Preventing Fe storage in endodermal vacuoles through vit1 mutation complemented the Fe mobilization defect in the nramp3/nramp4 double mutant under optimal growth conditions (Mary et al., 2015). Thus, VIT1 and NRAMP3/NRAMP4 play critical roles in the transport and distribution of metals in seeds, and regulating the expression of these transporters could lead to the development of better crops. Chloroplast metal homeostasis The chloroplast is separated from the cytosol by its outer and inner membranes. Inside the chloroplast, the thylakoid is also enclosed with a membrane. Metals are integral to chlorophyll biosynthesis and photosynthesis (Finazzi et al., 2015; López-Millán et al., 2016). The metal requirement of chloroplasts is very high, and so up to 80% of total leaf Fe and about 30% of leaf Cu are localized to chloroplasts (Schmidt et al., 2020). Within the chloroplast, Fe, Mn, and Cu mostly localize to thylakoids, where they participate in the photosynthetic electron transport chain. This high accumulation of transition metals is essential for photosynthesis and requires tightly regulated metal homeostasis to avoid ROS production. The roles of Fe, Mn, and Cu in photosynthesis and chloroplast metabolism have been comprehensively described (Nouet et al., 2011; López-Millán et al., 2016; Schmidt et al., 2020), and therefore we mainly focus on metal transport through the chloroplast membrane. The outer chloroplast membrane is permeable to metals, and therefore metal transport is regulated by the inner chloroplast membrane (Fig. 2). In Arabidopsis, the first step of Fe transport to chloroplast is performed by ferric chelate reductase oxidase 7 (FRO7), which reduces ferric iron to Fe2+ (Jeong et al., 2008; Jain et al., 2014). The reduced Fe2+ is then transported through a complex consisting of permease in chloroplasts 1 (PIC1) and nickel–cobalt transporter (NiCo). It seems that Fe2+ first binds to NiCo, then is transferred to PIC1 and subsequently transported through the inner chloroplast membrane (Duy et al., 2011; López-Millán et al., 2016; Schmidt et al., 2020). PIC1, NiCo, and FRO7 are co-expressed, strengthening the possibility that these genes work in coordination to regulate chloroplastic Fe transport (Schmidt et al., 2020). Changes in the expression of PIC1 affect chloroplast development and ultimately plant growth through reactions triggered by Fe toxicity or Fe deficiency, which suggests that reciprocal signaling occurs between the nucleus and chloroplast (Duy et al., 2011; López-Millán et al., 2016). Multiple antibiotic resistance 1 (MAR1; also named as IREG3) has been proposed to play a role in Fe transport to the chloroplast by transporting a molecule that chelates Fe, as MAR1 OX plants exhibit a deficient phenotype (Conte and Lloyd, 2010). The role of Arabidopsis mitoferrin-like 1 (AtMfl1) in Fe transport to chloroplasts has been described (Tarantino et al., 2011). atmfl1 mutants exhibit compromised growth, but direct evidence that AtMfl1 transports Fe remains elusive (Tarantino et al., 2011). In contrast to mobilization of vacuolar Fe (Conte et al., 2013), the roles of AtYSL4 and AtYSL6 in Fe export from the chloroplast to the intermembrane space have been described (Divol et al., 2013). YSL4 and YSL6 localize to chloroplasts in Arabidopsis and contribute to the release of NA-bound Fe from the chloroplasts. The release of chloroplastic Fe is critical to embryogenesis and senescence (Tarantino et al., 2011; Divol et al., 2013). Fig. 2. Open in new tabDownload slide Summary of metal transport in the chloroplast: proteins regulating micronutrient mineral transport in the chloroplast envelope and thylakoid. Examples of proteins that require metals for their function are shown. CCS, Cu chaperone for Cu/Zn-SOD; Cytb6f, cytochrome b6f; Fd, ferredoxin; FeRE, Fe-requiring enzymes; Fe–S clusters, iron–sulfur clusters, Fe molecules linked to sulfide that attach to proteins such as metalloproteins; FH, frataxin; MnRE, Mn-responsive enzymes; PC, plastocyanin; PetC, Rieske [2Fe–2S] protein; PSI, photosystem 1; PSII, photosystem II; SEC, secretion system; Tat, twin arginine translocase; TP, transfer proteins. Fig. 2. Open in new tabDownload slide Summary of metal transport in the chloroplast: proteins regulating micronutrient mineral transport in the chloroplast envelope and thylakoid. Examples of proteins that require metals for their function are shown. CCS, Cu chaperone for Cu/Zn-SOD; Cytb6f, cytochrome b6f; Fd, ferredoxin; FeRE, Fe-requiring enzymes; Fe–S clusters, iron–sulfur clusters, Fe molecules linked to sulfide that attach to proteins such as metalloproteins; FH, frataxin; MnRE, Mn-responsive enzymes; PC, plastocyanin; PetC, Rieske [2Fe–2S] protein; PSI, photosystem 1; PSII, photosystem II; SEC, secretion system; Tat, twin arginine translocase; TP, transfer proteins. Cu import into chloroplasts is mediated by a chloroplast-envelope P1B-type ATPase called HMA6/PAA1. HMA6 transports Cu+ into the chloroplast and is considered essential for photosynthesis (Shikanai et al., 2003; Catty et al., 2011; Boutigny et al., 2014). Cu may also be imported by HMA1, which transports Cu2+ to chloroplast (Boutigny et al., 2014). HMA1 and HMA6 represent distinct pathways for importing Cu, although the direction of HMA1 transport remains unclear (Boutigny et al., 2014). HMA1 and HMA6 double mutants do not exhibit a lethal phenotype, suggesting that other transporters also contribute to Cu import into the chloroplast (Catty et al., 2011; Boutigny et al., 2014). HMA8 (PAA2) transports Cu across the thylakoid membrane of the chloroplast (Aguirre and Pilon, 2016). The crystal structures of HMA6 and HMA8 have been reported (Mayerhofer et al., 2016). Recently, significant progress has been made in understanding Mn transport to plastids. Photosynthesis affected mutant 71 (PAM71) is an integral thylakoid membrane protein involved in Mn2+ and Ca2+ homeostasis in Arabidopsis chloroplasts (Eisenhut et al., 2018; Frank et al., 2019). It complements the Mn-hypersensitive yeast mutant Δpmr1, suggesting that it functions in Mn2+ uptake into thylakoids to support optimal PSII performance (Schneider et al., 2016). In addition, Arabidopsis chloroplast Mn transporter 1 (CMT1) is involved in chloroplast Mn homeostasis (Eisenhut et al., 2018; Schmidt et al., 2020). It is the closest homolog of PAM71, and in contrast to PAM71, is localized to the chloroplast envelope. CMT1 is expressed ubiquitously, but its expression is down-regulated under excess Mn conditions. Like PAM71, the expression of CMT1 can also complement the Mn-hypersensitive phenotype of Δpmr1 yeast. The cmt1 mutant exhibits severely suppressed growth along with defects in chloroplast ultrastructure and PSII activity caused by decreased levels of pigments and thylakoid membrane proteins. The pam71/cmt1–1 double mutant exhibits a phenotype similar to that of the cmt1–1 single mutant. These results clearly indicate that CMT1 and PAM71 work in coordination to deliver Mn to PSII across the chloroplast envelope and the thylakoid membrane, thereby ensuring Mn homeostasis in chloroplasts (Eisenhut et al., 2018; Schmidt et al., 2020). Zn transport to and from the chloroplast is not comprehensively understood. HMA1 and HMA6 have broad substrate ranges and may transport Zn in addition to Cu (Williams and Mills, 2005; Kim et al., 2009; Catty et al., 2011; Boutigny et al., 2014). The roles of other transporters in Zn transport to the chloroplast remain unclear. Elucidating the role of chloroplastic metal transporters would provide opportunities for regulating the expression of these transporters for crop improvement. Orchestrating the movement of metals into and out of chloroplast could significantly improve photosynthesis and cellular metabolism, improving plant growth. Ferritin is considered the main Fe storage protein, as it maintains a large Fe core in its cavity and has ferroxidase activity. In plants, ferritin is mainly localized to chloroplasts, although mitochondrial localization has also been reported (Zancani et al., 2004). Therefore, chloroplasts serve as a storage hub for Fe, particularly during early plant growth (Briat et al., 2010). Arabidopsis harbors four ferritin genes, while rice processes two copies of ferritin. Regulating the expression of ferritin is a common strategy for biofortification in plants and could also be helpful for regulating plant growth under varying Fe availability conditions (Masuda et al., 2013). Clarifying how plants choose the directional movement of Fe to the chloroplast or vacuole is an interesting topic for future research. Ferritins control the interaction between Fe homeostasis and oxidative stress in Arabidopsis and therefore are a good indicator of stress signaling in plants (Ravet et al., 2009, 2012). Mitochondrial metal homeostasis Mitochondria are considered the powerhouse of the cell due to their central role in providing energy molecules such as ATP and various metabolites that are essential to the regulation of cellular growth. Mitochondria also regulate metabolic pathways in the cytoplasm and various subcellular organelles such as the chloroplast through their regulation of energy production, metabolites such as citrate and acetate, and Fe–S cluster synthesis (Vigani et al., 2013b, 2016). Mitochondria are enclosed with two membranes, known as the outer and inner mitochondrial membranes. Mitochondria maintain their function through intensive communication with the cytosol as well as other organelles. Transport of metabolites and inorganic ions across the two membranes occurs through specific ion channels and transporters, which play a crucial role in ensuring sufficient ionic and metabolite concentrations within the mitochondria (Vothknecht and Szabo, 2020). Thus, mitochondria may serve as an indicator of cellular metabolic status (Sweetlove et al., 2007; Millar et al., 2011; Bashir et al., 2016; Vigani et al., 2016). Changes in metabolic energy status force mitochondria to reconfigure their metabolism, which ultimately affects photosynthesis and/or nuclear gene expression (Schwarzländer et al., 2012; Vigani et al., 2013b, 2016, 2019; Bashir et al., 2016; Vigani and Hanikenne, 2018). The outer mitochondrial membrane has pores large enough to allow the movement of metal ions, small molecules, and small proteins or peptides (Vigani et al., 2019). Thus, the responsibility for regulating ion flow in and out of mitochondria is served by the inner membrane, which harbors proteins involved in electron transport and ATP synthesis. Mitochondria play a critical role in the synthesis and assembly of Fe–S cluster (ISC) machinery, heme and other lipoic acid cofactors (Lill et al., 2015). Assembly of nuclear and cytosolic Fe/S proteins depends on mitochondrial S-containing compounds (Lill et al., 2015). Regulation of the redox status of mitochondria is important for several processes, not only within the mitochondria, but also for the overall cellular metabolism. Arabidopsis ATM3 (also known as STA1) appears to be involved in export of glutathione (GSH)/GSH trisulfide complexes from the mitochondria to the cytoplasm (Schaedler et al., 2014). Disrupting the export of these complexes significantly affects Fe–S cluster assembly in the cytosol (Kushnir et al., 2001; Bernard et al., 2009; Teschner et al., 2010). In addition to regulating redox status and a role in mitochondrial Fe–S cluster assembly, GSH has been suggested to play an important role in the plant response to metal homeostasis (Bashir et al., 2007; Shanmugam et al., 2015). In Arabidopsis, GSH plays an important role in NO-mediated Fe-deficiency signaling and Fe-deficiency tolerance (Shanmugam et al., 2015). In Arabidopsis, glutathione reductase 2 (GR2) is indispensable for maintaining the optimal redox potential in the chloroplast. Mitochondrial glutathione disulfide (GSSG) may be exported to the cytosol in an effort to maintain the mitochondrial redox potential, and ATM3 may play a role in this process (Marty et al., 2019). Rice mitochondrial OsATM3 is essential for cytosolic Fe–S cluster assembly and meristem maintenance in rice (Oryza sativa). Loss of function of OsATM3 is lethal in rice at the four-leaf stage (Zuo et al., 2017). Cytosolic iron-sulfur protein activities are also significantly compromised in both knockout and knockdown lines of OsATM3. The expression profiles of several Fe metabolism-related genes are altered in OsATM3 knockout and knockdown lines, whereas only minor effects were observed in Arabidopsis ATM3 mutants (Bernard et al., 2009; Zuo et al., 2017). Impairment of glutathione metabolism, production of ROS and changes in the expression of Fe metabolism-related genes indicate that OsATM3 is essential for Fe homeostasis in rice (Zuo et al., 2017). Metal transport in plant mitochondria has not yet been fully clarified (Fig. 3). Arabidopsis ferric reduction oxidases 3 and 8 (FRO3 and FRO8) localize to the mitochondria and are involved in ferric reduction, thereby contributing to mitochondrial Fe transport in plants (Jain et al., 2014). Mitochondrial Fe transporters (MITs) have been characterized in rice and Arabidopsis. Rice has one gene involved in mitochondrial metal uptake, while Arabidopsis harbors two. As rice possesses a single copy of this gene, it is not surprising that it is essential for growth and development. A rice MIT knockout mutant (mit-1) exhibits a lethal phenotype, while an MIT knockdown mutant (mit-2) exhibits stunted growth and reduced chlorophyll. Although mit-2 plants accumulate higher levels of Fe and Mn in their shoots, their mitochondrial Fe and Mn contents are significantly reduced. Despite having higher Fe levels in leaves, mutant plants exhibit symptoms of Fe deficiency, i.e. up-regulation of Fe deficiency-related genes and chlorotic leaves (Bashir et al., 2011a, c; Vigani et al., 2016). Disruption of MIT function also alters cellular respiration and affects aconitase activity at the cellular and mitochondrial levels. Therefore, MIT has been suggested to affect synthesis of the Fe–S cluster at the cellular and mitochondrial levels (Bashir et al., 2011c; Vigani et al., 2016). Mn accumulation in shoot tissues and accumulation of Mn and Cu in mitochondria isolated from shoots of mit-2 plants were significantly altered (Bashir et al., 2011c). These changes could be attributed to either reduced transport to mitochondria or up-regulation of metal transporters that deposit metals in other subcellular compartments, such as OsVIT2. Arabidopsis MIT1 and MIT2 are essential to Fe homeostasis (Jain et al., 2019). In contrast to rice, Arabidopsis mit1 and mit2 mutants accumulate less Fe in leaves, while accumulating more cobalt, Cu, Zn, and Mn relative to wild-type plants. Similarly, mitochondrial Fe content was decreased and Zn concentration increased in mutants with compromised mitochondrial Fe transporters. It is unclear why rice has only one mitochondrial Fe transporter while Arabidopsis possesses two copies. In rice as well as in Arabidopsis, regulation of MIT proteins alters metal accumulation in seeds; therefore, fine-tuning of mitochondrial proteins might be useful for biofortification and for optimizing plant growth and development. Other proteins directly involved in mitochondrial Cu, Mn, or Zn import have not yet been reported in plants, and identification of these proteins is a prerequisite to the development of innovative crop improvement strategies related to metal transport. Fig. 3. Open in new tabDownload slide Metal transport in the mitochondrion: proteins regulating micronutrient mineral transport in the mitochondrion. Examples of proteins that require metals for their function are shown. All proteins in the figure are from Arabidopsis except MIT(Os) and OsATM3, which are rice proteins. Cyt c, cytochrome c; GSSG complexes, glutathione complexes; Heme, an iron-containing compound of the porphyrin class that forms the non-protein component of hemoglobin and other biological molecules. Fig. 3. Open in new tabDownload slide Metal transport in the mitochondrion: proteins regulating micronutrient mineral transport in the mitochondrion. Examples of proteins that require metals for their function are shown. All proteins in the figure are from Arabidopsis except MIT(Os) and OsATM3, which are rice proteins. Cyt c, cytochrome c; GSSG complexes, glutathione complexes; Heme, an iron-containing compound of the porphyrin class that forms the non-protein component of hemoglobin and other biological molecules. Mitochondrial Cu chaperones are important for mitochondrial function due to their role in biogenesis of cytochrome c oxidase (COX), which is the final electron acceptor in the respiratory chain involved in reduction of O2 to H2O. The roles of several COX proteins in regulating cellular Cu and/or Fe homeostasis have been described (Yamasaki et al., 2007; Radin et al., 2015; Garcia et al., 2019). COX11 is an essential COX complex assembly factor in Arabidopsis and plays an important role in pollen germination and plant growth (Radin et al., 2015). Similarly, COX19 plays a critical role in regulating Fe and Cu homeostasis (Garcia et al., 2019). In addition to transporters and chaperones, mitochondrial ferritin and frataxin also contribute to mitochondrial metal homeostasis. Plant frataxins are engaged in several functions involving the Fe–S cluster assembly machinery and are also involved in heme biosynthesis (Armas et al., 2019). In Arabidopsis, Ferritin 4 (AtFer-4) is localized to the mitochondria (Murgia and Vigani, 2015). Although impairment of ferritin or frataxin does not alter mitochondrial respiration, the distribution of macro- and microelements is significantly altered in their mutants (Murgia and Vigani, 2015). Arabidopsis plants with defective frataxin exhibit an embryonic lethal phenotype (Murgia and Vigani, 2015). Mitochondrial Fe-regulated (MIR) protein is specifically found in rice and plays a critical yet undefined role in mineral homeostasis. Expression of MIR is significantly up-regulated in response to Fe deficiency. MIR knockout mutants accumulate higher levels of Fe in shoots and exhibit altered expression of metal homeostasis-related genes (Ishimaru et al., 2009). MIR appears to be highly specific to rice, as its homologs have not been identified in any other crop species (Ishimaru et al., 2009). MIR has been suggested to function as a critical component of the Fe-deficiency response in the AA genomic subgroup of genus Oryza. MIR was suggested to have evolved through duplication of the exon sequence of a raffinose synthesis gene in a stepwise process (de Oliveira et al., 2020). Elucidation of the exact function of MIR remains a challenge, and such information could significantly contribute to clarifying mitochondrial Fe regulation in rice. In general, mitochondrial metal uptake is poorly understood, particularly in terms of cellular, vacuolar and chloroplastic metal uptake processes. Based on the current state of knowledge, regulation of metal homeostasis via MIT, MIR, and FRO proteins is likely to significantly enhance mitochondrial function, improving plant metabolism and thus crop production. Mineral transport in the endomembrane system The plant endomembrane system consists of the nuclear membrane, endoplasmic reticulum (ER), Golgi apparatus, vacuoles, lysosomes, small vesicles, endosomes, and plasma membrane (Morita and Shimada, 2014). Metal distribution to the endomembrane system is crucial to cellular metabolism (Fig. 4), and various transporter proteins localized to these compartments have been described in plants (Roschzttardtz et al., 2011; Seo et al., 2012; Menguer et al., 2018; Zhang and Liu, 2017; Ma et al., 2018; Tsunemitsu et al., 2018). In the Golgi apparatus, several glycosyl transferases require Mn for maintenance of their function, and some of these enzymes contribute to the synthesis of cell wall polysaccharides (Porchia et al., 2002). Moreover, excess metals might also be stored in the Golgi apparatus (Pedas et al., 2014). Biosynthesis of the metal chelators NA and MAs involves small vesicles, and secretion of MAs also occurs through the endomembrane system (Nishizawa and Mori, 1987; Negishi et al., 2002; Bashir et al., 2006, 2017; Bashir and Nishizawa, 2006; Nozoye et al., 2014). Fig. 4. Open in new tabDownload slide Metal transport in the endomembrane system of plant cells: proteins regulating micronutrient mineral transport in the endomembrane system. ER, endoplasmic reticulum; GC, Golgi complex; NA, nicotianamine. Fig. 4. Open in new tabDownload slide Metal transport in the endomembrane system of plant cells: proteins regulating micronutrient mineral transport in the endomembrane system. ER, endoplasmic reticulum; GC, Golgi complex; NA, nicotianamine. The nucleus contains a significant amount of Fe (Roschzttardtz et al., 2011); however, it remains unclear whether transporters involved in transport of Fe or other metals into the nucleus occur in plants. The pore size of the nuclear envelope is large enough to allow the movement of metal ions. However, an excess of metals can be extremely toxic for the nucleus, and therefore the nucleus likely regulates the movement of metal ions. Arabidopsis IRT2 is localized to vesicles within root epidermal cells (Conte and Walker, 2011); AtIRT2 transports Fe2+, and its expression is regulated by Fe deficiency. Barley YSL5 is localized to vesicle membranes, and its expression is specifically induced by Fe deficiency. HvYSL5 has been suggested to play a role in transient storage of Fe, MAs, or both (Zheng et al., 2011). Rice OsYSL5 and OsYSL6 might contribute to the transport of metal–NA or metal–DMA complexes into internal compartments (Sasaki et al., 2011). In phylogenetic analyses, OsYSL5/OsYSL6 and HvYSL5 form a distinct clade with Arabidopsis YSL4/YSL6. All transporters in this clade have been proposed to regulate subcellular metal homeostasis in plants (Aoyama et al., 2009; Zheng et al., 2011). Several transporters contribute to mineral transport to the ER or Golgi complex. Arabidopsis MTP11 is localized to pre-vacuolar or Golgi-like compartments and confers tolerance to excess Mn through vesicular trafficking and subsequent exocytosis of excess Mn (Peiter et al., 2007). mtp11 mutants are hypersensitive to excess Mn, while MTP11 OX plants are tolerant of excess Mn (Delhaize et al., 2007; Peiter et al., 2007). MTP11 orthologs in other species are also localized to Golgi-like compartments. OsMTP11 is a trans-Golgi network-localized Mn transporter that plays a role in Mn tolerance through intracellular Mn compartmentalization. It contributes to maintaining high fertility in rice, as revealed by the decreased grain yield and fertility of the mtp11 mutant (Zhang and Liu, 2017). MTP8.1 and MTP8.2 are localized to the Golgi complex in barley and contribute to Mn efflux (Pedas et al., 2014). Arabidopsis NRAMP2 is a trans-Golgi network-localized Mn transporter that positively contributes to the Arabidopsis root growth under Mn-deficient conditions (Alejandro et al., 2017; Gao et al., 2018). Arabidopsis IAR1 has been suggested to transport Zn to the ER (Lasswell et al., 2000). Arabidopsis HMA7 (also called RAN1) is a Cu transporter that contributes to the biogenesis of ethylene receptors and Cu homeostasis in Arabidopsis seedlings (Binder et al., 2010). Arabidopsis ECA1 pumps Mn2+ into the ER, which supports plant growth under conditions of Mn2+ toxicity (Wu et al., 2002), while ECA3 pumps Mn2+ into Golgi bodies (Mills et al., 2008). Mineral transport to the Golgi apparatus is essential to several physiological processes, including ROS production, root growth and seed fertility. Therefore, regulating the transport of metals to the Golgi complex could be used as a tool for crop improvement. Regulating metal homeostasis could significantly improve plant growth Numerous approaches have been utilized to improve plant growth under limited metal availability, abiotic stresses, or other challenging environmental conditions (Bashir et al., 2016, 2019a; Masuda et al., 2017; Aung et al., 2019). Regulation of metal uptake and distribution is extremely sensitive, as an excess of metals may trigger the production of ROS, thereby limiting plant growth and development. Therefore, multiple metal chelators are required at optimal concentrations to positively regulate cellular metal distribution and availability (Bashir et al., 2013a, 2016; Clemens, 2019). Similarly, the distribution of metals among tissues or compartments has been visualized using various techniques. This information enables the development of strong strategies for the improvement of crops based on the optimal distribution and proper utilization of metals. Strategies for breeding crop plants to tolerate a particular environmental condition could be employed. As most chloroplastic and mitochondrial proteins are encoded in the nucleus, chloroplasts and mitochondria must maintain a comprehensive communication system to regulate nuclear gene expression (Kleine and Leister, 2016). Signaling from the chloroplast or mitochondria to the nucleus, known as retrograde signaling, is essential to coordinating the expression of components involved in photosynthesis, respiration, and other metabolic processes. Metal availability is essential for the maintenance of an optimal metabolic rate, and therefore it is reasonable to assume that mineral distribution is regulated in a similar manner (Vigani et al., 2013b). Several types of signals could be coordinated to regulate metal homeostasis (Fig. 5). Subcellular organelles such as mitochondria and the cytoplasm depend on energy harvest by chloroplasts (Raghavendra and Padmasree, 2003; Zhao et al., 2020). Chloroplastic metabolites could play a role in regulating the cellular metabolism and thus indirectly regulating cellular metal homeostasis. Transcription factors and ubiquitin ligases have been suggested as the primary regulators of Fe signaling in the nucleus (Kobayashi, 2019). Manipulation of these regulators is an effective method for producing crops with altered metal homeostasis, improved growth under nutrient limitation, and greater metal accumulation in edible parts. In particular, knockdown of HRZ ubiquitin ligases in rice results in improved growth under Fe limitation as well as accumulation of Fe and Zn in the shoots and seeds without any growth reduction under various conditions (Kobayashi et al., 2013; Aung et al., 2018). As maintenance of low ROS levels inside the cell is a prerequisite for optimal metabolism and the availability of free metals contributes to ROS production, ROS-driven redox changes could reasonably contribute to signaling for regulation of subcellular metal homeostasis. Intracellular redox compartmentalization and ROS-related communication are integral steps in cell signaling in response to various environmental factors, and ROS produced at different subcellular sites can trigger distinct transcriptomic responses (Gadjev et al., 2006; Noctor and Foyer, 2016). Fig. 5. Open in new tabDownload slide Putative signaling pathway regulating metal homeostasis in plant cell. The putative signaling pathway regulating cellular mineral transport is shown. Metals, reactive oxygen species, Fe–S clusters, photosynthetic metabolites, transcriptional regulation, and retrograde signaling processes such as PAP signaling may regulate cellular metal homeostasis. Fig. 5. Open in new tabDownload slide Putative signaling pathway regulating metal homeostasis in plant cell. The putative signaling pathway regulating cellular mineral transport is shown. Metals, reactive oxygen species, Fe–S clusters, photosynthetic metabolites, transcriptional regulation, and retrograde signaling processes such as PAP signaling may regulate cellular metal homeostasis. Crosstalk between various components of chloroplastic and vacuolar metal transporters such as VIT1, NRAMP3/4, YSL4/6, and ferritin has been suggested to regulate metal release from the vacuole for use in the chloroplast or deposition in the seeds (Vigani et al., 2019). Based on the phenotypes of various mutants related to mitochondrial function, mitochondria or other cellular organelles have been suggested to regulate retrograde signaling pathways and thus control metal deficiency-induced signaling (Vigani et al., 2013a, b, 2019). Recently, it was suggested that the 3′-phosphoadenosine 5′-phosphate (PAP)/SAL retrograde signaling pathway regulates ethylene signaling and Fe metabolism. This pathway utilizes PAP, which is regulated by SAL1/FRY1, and occurs in chloroplasts and mitochondria (Balparda et al., 2020). Recently, peptides in the IRON MAN (IMA)/Fe uptake-inducing peptide (FEP) family were reported to function in the regulation of Fe uptake and homeostasis in Arabidopsis and rice (Grillet et al., 2018; Hirayama et al., 2018; Kobayashi et al., 2021). Such peptides may also contribute to subcellular metal homeostasis. Comprehensive characterization of mit-2 mutants through transcriptomic and metabolomic analyses suggests that cellular gene expression and metabolism are regulated through retrograde signaling between the mitochondria and nucleus (Vigani et al., 2016). These analyses also suggest that mitochondrial function adapts to variation in the energy needs of tissues, as changes in roots and shoots are differentially regulated in mit-2 mutants. Considering the role of MIT in rice, shoot mitochondria appear to require more Fe than roots, as more metabolic changes were observed in shoot tissues relative to roots (Vigani et al., 2016). A rice mutant lacking oligopeptide transporter 7 (opt7–1) accumulated twice as much Fe in its shoots as wild-type plants (Bashir et al., 2015). Although this phenotype is similar to that of mit-2 plants (Bashir et al., 2011c), the transcriptomic changes observed in opt7–1 plants are strikingly different from those observed in mit-2 plants. This difference can be attributed to the fact that mitochondrial Fe transport is not affected in the opt7–1 mutant. In the mit-2 mutant, surplus Fe is thought to be stored in vacuoles, as indicated by the up-regulation of OsVIT2, whereas in the osopt7–1 mutant, the additional Fe is localized to the chloroplast and the expression and activity of ferritin increase significantly (Bashir et al., 2011c, 2015; Vigani et al., 2016). Similarly, defective seed Fe mobilization in the nramp3/nramp4 double mutant strongly affects plastids, but not mitochondria (Bastow et al., 2018). These results suggest that moderate enhancement of the availability of metals to various subcellular compartments could significantly improve cellular metabolism (Bashir et al., 2014, 2016). Rice aconitase 1 (OsACO1) was recently reported to play a role in regulating metal homeostasis. OsACO1 has been suggested to regulate the Fe deficiency response either through an enzymatic reaction catalysing the isomerization of citrate, or through specific RNA binding for post-transcriptional regulation of genes involved in Fe homeostasis such as OsOPT7 (Senoura et al., 2020). Seed metal localization in Arabidopsis and rice can be significantly altered by regulating the expression of vacuolar or mitochondrial metal transporters (Kim et al., 2006; Zhang et al., 2012; Bashir et al., 2013b; Mary et al., 2015; Chu et al., 2017; Jain et al., 2019). Subcellular metal transporters also contribute to better plant growth through their roles in processes related to seedling development, root growth, and seed fertility (Mary et al., 2015; Bastow et al., 2018; Gao et al., 2018; Ma et al., 2018). Several biotic and abiotic stresses result in altered expression of genes involved in metal accumulation or homeostasis (Expert et al., 2012; Lei et al., 2014; Rasheed et al., 2016; Bashir et al., 2019a). Thus, efficiently regulating subcellular metal transport or distribution would enable plants to exhibit tolerance to various biotic and abiotic stresses. Their growth could be improved under a broad range of environmental conditions, and improvement in metal accumulation in seeds for biofortification purposes could also be achieved. Under conditions of metal toxicity, the expression of metal chelators and ferritin along with vacuolar transporter proteins could be employed to improve plant growth, biomass, and ultimately yield. Regulating the expression of VIT1 and NRAMP3/NRAMP4 or VIT1/VIT2 and MIT in rice could contribute to the biofortification of seeds (Zhang et al., 2012; Gollhofer et al., 2014; Mary et al., 2015; Bastow et al., 2018; Bashir et al., 2019b). Specifically modifying an organelle transporter to tolerate the toxicity of a particular metal would help to avoid mismetalation and could also significantly improve plant growth. Expressing the modified version of transporters, as well as regulating the expression of transporters, metal chelators, or metal storage proteins, could be utilized to improve metal availability or utilization and thus increase crop production. Improving the substrate specificity of transporter proteins could also significantly contribute to optimal metal uptake and distribution, and ultimately to improved metabolism and plant growth. Conclusions Optimal subcellular regulation of Fe and its interactions with Zn, Cu, and Mn are important for plant growth, development, and biofortification. Regulation of metal uptake and distribution must be extremely sensitive, as excess metals might trigger the production of ROS, which limit plant growth and development. Therefore, different metal chelators are required at optimal concentrations to efficiently regulate the cellular distribution and availability of metals. Our understanding of metal ligands has improved significantly in recent years (Clemens, 2019). Similarly, the distribution of metals among tissues or compartments has been visualized through various techniques utilizing mutants. The information thus obtained enables strategies for development of better crops to be strengthened through optimal metal distribution and utilization. Consequently, further efforts are required to improve our understanding of mineral transport to the mitochondrion, chloroplast, and other subcellular organelles such as peroxisomes. In particular, a major effort is needed to elucidate Zn transport to these organelles. Moreover, the speciation of metals transported by various transporters, such as MIT, should be elucidated and the exact physiological roles of these transporters should be revealed. Elucidation of the roles of non-coding RNA, small peptides, and epigenomic regulation in metal homeostasis is also important. Similarly, further investigations into metal sensing and signaling in plants are needed for further improvement of crop plants. Understanding cellular metal homeostasis under drought, heat, and other stresses, such as insect pest attack, is also important in improving crop production under challenging environmental conditions. Rapidly changing environmental stresses significantly affect plant growth, and the combination of these environmental stresses with metal deficiency or toxicity significantly compromises plant growth; e.g. moderate drought stress combined with metal-deficient conditions may severely affect plant growth. Therefore, understanding Fe transport and its interactions with Cu, Mn, and Zn homeostasis under multiple stress conditions is extremely difficult. These advances would facilitate the development of crop plants exhibiting efficient metal storage and distribution that are able to grow well under challenging environmental conditions. Acknowledgements The authors are thankful to all of their coworkers who maintained an efficient working environment to support this research during the current pandemic. Author contributions KB wrote the manuscript. ZA prepared the figures. ZA, TK, MS, and NKN critically read the manuscript and contributed to improve it. References Aguirre G , Pilon M. 2016 . Copper delivery to chloroplast proteins and its regulation . Frontiers in Plant Science 6 , 1250 . Google Scholar OpenURL Placeholder Text WorldCat Alejandro S , Cailliatte R, Alcon C, Dirick L, Domergue F, Correia D, Castaings L, Briat JF, Mari S, Curie C. 2017 . Intracellular distribution of manganese by the trans-Golgi network transporter NRAMP2 is critical for photosynthesis and cellular redox homeostasis . The Plant Cell 29 , 3068 – 3084 . 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TI - Roles of subcellular metal homeostasis in crop improvement
JO - Journal of Experimental Botany
DO - 10.1093/jxb/erab018
DA - 2021-01-27
UR - https://www.deepdyve.com/lp/oxford-university-press/roles-of-subcellular-metal-homeostasis-in-crop-improvement-aeLMecLUjK
SP - 1
EP - 1
VL - Advance Article
IS - 
DP - DeepDyve
ER -