The mitochondrial aspartate/glutamate carrier (AGC or Aralar1) isoforms in D. melanogaster: biochemical characterization, gene structure, and evolutionary analysis

Lunetti, Paola; Marsano, Renè Massimiliano; Curcio, Rosita; Dolce, Vincenza; Fiermonte, Giuseppe; Cappello, Anna Rita; Marra, Federica; Moschetti, Roberta; Li, Yuan; Aiello, Donatella; Martínez, Araceli del Arco; Lauria, Graziantonio; Leonardis, Francesco De; Ferramosca, Alessandra; Zara, Vincenzo; Capobianco, Loredana

doi:10.1016/j.bbagen.2021.129854

Cited by 11 publications

(10 citation statements)

References 88 publications

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“…The unidirectional efflux of labeled aspartate from proteoliposomes did not significantly change if a 1.5 unit of ΔpH (▼) (6.5 inside and 8 outside) was applied across the proteoliposomal membrane, thus suggesting that DmUCP4A is able to catalyze an electrogenic rather than a proton-assisted uniport of aspartate (Figure 3B). We were unable to dissect this point further by generating a valinomycin-dependent K + -diffusion potential across the proteoliposomal membrane [6,26], since the high concentrations of KCl required in these kinds of experiments interfered with DmUCP4A transport activity.…”

Section: Kinetic Properties Of the Recombinant Dmucp4a Proteinmentioning

confidence: 99%

“…A W303 (wild-type) (MATa {leu2-3112 trp1-1 can1-100 ura3-1 ade2-1 his3-11,15}) yeast strain was provided by the EUROFAN resource center EUROSCARF (Frankfurt, Germany). The yeast gene deletions (agc1∆ and agc1∆/ymc2∆) were achieved as described before [26,33]. The recombinant DmUCP4A-pYES2_TD3H [33] and pRS416 plasmids, without or with the coding sequence of AGC1p, respectively, were introduced into the agc1∆ yeast strain.…”

Section: Yeast Strains Growth Conditions and Functional Complementationmentioning

confidence: 99%

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Drosophila melanogaster Uncoupling Protein-4A (UCP4A) Catalyzes a Unidirectional Transport of Aspartate

Lunetti

Gorgoglione

Curcio

et al. 2022

IJMS

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Uncoupling proteins (UCPs) form a distinct subfamily of the mitochondrial carrier family (MCF) SLC25. Four UCPs, DmUCP4A-C and DmUCP5, have been identified in Drosophila melanogaster on the basis of their sequence homology with mammalian UCP4 and UCP5. In a Parkinson’s disease model, DmUCP4A showed a protective role against mitochondrial dysfunction, by increasing mitochondrial membrane potential and ATP synthesis. To date, DmUCP4A is still an orphan of a biochemical function, although its possible involvement in mitochondrial uncoupling has been ruled out. Here, we show that DmUCP4A expressed in bacteria and reconstituted in phospholipid vesicles catalyzes a unidirectional transport of aspartate, which is saturable and inhibited by mercurials and other mitochondrial carrier inhibitors to various degrees. Swelling experiments carried out in yeast mitochondria have demonstrated that the unidirectional transport of aspartate catalyzed by DmUCP4 is not proton-coupled. The biochemical function of DmUCP4A has been further confirmed in a yeast cell model, in which growth has required an efflux of aspartate from mitochondria. Notably, DmUCP4A is the first UCP4 homolog from any species to be biochemically characterized. In Drosophila melanogaster, DmUCP4A could be involved in the transport of aspartate from mitochondria to the cytosol, in which it could be used for protein and nucleotide synthesis, as well as in the biosynthesis of ß-alanine and N-acetylaspartate, which play key roles in signal transmission in the central nervous system.

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Section: Kinetic Properties Of the Recombinant Dmucp4a Proteinmentioning

confidence: 99%

Section: Yeast Strains Growth Conditions and Functional Complementationmentioning

confidence: 99%

Drosophila melanogaster Uncoupling Protein-4A (UCP4A) Catalyzes a Unidirectional Transport of Aspartate

Lunetti

Gorgoglione

Curcio

et al. 2022

IJMS

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“…Each experiment was repeated at least 3 times [ 71 , 72 ]. The comparative threshold cycle method was used in relative gene quantification, as previously described [ 73 , 74 ], using Peptidylprolyl isomerase A ( PPIA ).…”

Section: Methodsmentioning

confidence: 99%

A Picrocrocin-Enriched Fraction from a Saffron Extract Affects Lipid Homeostasis in HepG2 Cells through a Non-Statin-like Mode

Frattaruolo

Marra

Lauria

et al. 2023

IJMS

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Dyslipidemia is a lipid metabolism disorder associated with the loss of the physiological homeostasis that ensures safe levels of lipids in the organism. This metabolic disorder can trigger pathological conditions such as atherosclerosis and cardiovascular diseases. In this regard, statins currently represent the main pharmacological therapy, but their contraindications and side effects limit their use. This is stimulating the search for new therapeutic strategies. In this work, we investigated in HepG2 cells the hypolipidemic potential of a picrocrocin-enriched fraction, analyzed by high-resolution 1H NMR and obtained from a saffron extract, the stigmas of Crocus sativus L., a precious spice that has already displayed interesting biological properties. Spectrophotometric assays, as well as expression level of the main enzymes involved in lipid metabolism, have highlighted the interesting hypolipidemic effects of this natural compound; they seem to be exerted through a non-statin-like mechanism. Overall, this work provides new insights into the metabolic effects of picrocrocin, thus confirming the biological potential of saffron and paving the way for in vivo studies that could validate this spice or its phytocomplexes as useful adjuvants in balancing blood lipid homeostasis.

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“…AGC1 is mainly expressed in heart, skeletal muscle, and brain whereas AGC2 is expressed in many tissues and abundantly in liver [ 77 , 78 ]. In vitro, both isoforms catalyse a Ca 2+ -stimulated electrogenic exchange of mitochondrial aspartate for cytosolic glutamate plus a proton [ 76 , 79 ]. AGC, together with the mitochondrial oxoglutarate/malate carrier [ 80 , 81 ], the two isoforms of malate dehydrogenase and glutamic-oxaloacetic transaminase, constitute the malate-aspartate shuttle (MAS) which transfers NADH reducing equivalents from cytosol to mitochondria [ 82 , 83 ].…”

Section: The Mitochondrial Aspartate/glutamate Carrier: a Key Player Of Malate-aspartate Shuttlementioning

confidence: 99%

Glutamine-Derived Aspartate Biosynthesis in Cancer Cells: Role of Mitochondrial Transporters and New Therapeutic Perspectives

Gorgoglione

Impedovo

Riley

et al. 2022

Cancers

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Aspartate has a central role in cancer cell metabolism. Aspartate cytosolic availability is crucial for protein and nucleotide biosynthesis as well as for redox homeostasis. Since tumor cells display poor aspartate uptake from the external environment, most of the cellular pool of aspartate derives from mitochondrial catabolism of glutamine. At least four transporters are involved in this metabolic pathway: the glutamine (SLC1A5_var), the aspartate/glutamate (AGC), the aspartate/phosphate (uncoupling protein 2, UCP2), and the glutamate (GC) carriers, the last three belonging to the mitochondrial carrier family (MCF). The loss of one of these transporters causes a paucity of cytosolic aspartate and an arrest of cell proliferation in many different cancer types. The aim of this review is to clarify why different cancers have varying dependencies on metabolite transporters to support cytosolic glutamine-derived aspartate availability. Dissecting the precise metabolic routes that glutamine undergoes in specific tumor types is of upmost importance as it promises to unveil the best metabolic target for therapeutic intervention.

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The mitochondrial aspartate/glutamate carrier (AGC or Aralar1) isoforms in D. melanogaster: biochemical characterization, gene structure, and evolutionary analysis

Cited by 11 publications

References 88 publications

Drosophila melanogaster Uncoupling Protein-4A (UCP4A) Catalyzes a Unidirectional Transport of Aspartate

Drosophila melanogaster Uncoupling Protein-4A (UCP4A) Catalyzes a Unidirectional Transport of Aspartate

A Picrocrocin-Enriched Fraction from a Saffron Extract Affects Lipid Homeostasis in HepG2 Cells through a Non-Statin-like Mode

Glutamine-Derived Aspartate Biosynthesis in Cancer Cells: Role of Mitochondrial Transporters and New Therapeutic Perspectives

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