Structure and function of mitochondrial carriers – Role of the transmembrane helix P and G residues in the gating and transport mechanism

Palmieri, Ferdinando; Pierri, Ciro Leonardo

doi:10.1016/j.febslet.2009.10.063

Cited by 116 publications

(128 citation statements)

References 51 publications

(100 reference statements)

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“…It was recognized at the time of the sequencing that PiC is structurally similar to other IMM carrier proteins, the ANT and UCP1 (uncoupling protein 1) [29,34]. This cohort of IMM proteins is known as mitochondrial carrier (MC) proteins [35,36] [37].…”

Section: Cloning and Molecular Characterization Of The Pic Proteinmentioning

confidence: 99%

The mitochondrial phosphate carrier: Role in oxidative metabolism, calcium handling and mitochondrial disease

Seifert

Ligeti

Mayr

et al. 2015

Biochemical and Biophysical Research Communications

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The mitochondrial phosphate carrier (PiC) is a mitochondrial solute carrier protein, which is encoded by SLC25A3 in humans. PiC delivers phosphate, a key substrate of oxidative phosphorylation, across the inner mitochondrial membrane. This transport activity is also relevant for allowing effective mitochondrial calcium handling.Furthermore, PiC has also been described to affect cell survival mechanisms via interactions with cyclophilin D and the viral mitochondrial-localized inhibitor of apoptosis (vMIA). The significance of PiC has been supported by the recent discovery of a fatal human condition associated with PiC mutations. Here, we present first the early studies that lead to the discovery and molecular characterization of the PiC, then discuss the very recently developed mouse models for PiC and pathological mutations in the human SLC25A3 gene.

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Section: Cloning and Molecular Characterization Of The Pic Proteinmentioning

confidence: 99%

The mitochondrial phosphate carrier: Role in oxidative metabolism, calcium handling and mitochondrial disease

Seifert

Ligeti

Mayr

et al. 2015

Biochemical and Biophysical Research Communications

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“…These data are consistent with the inability of these mutant proteins to rescue the shawn mutant phenotypes. The mutations in sh 1 and sh 2 reside in evolutionary well conserved motifs: sh 1 affects a G-X-X-X-G motif involved in the stabilization of transmembrane helix-helix interactions (Senes et al, 2000), whereas sh 2 disrupts a glycine-proline hinge region (PX[D/E]XX[K/R]), thought to be necessary for carrier function (Palmieri and Pierri, 2010; Fig. 4B).…”

Section: Shawn Is a Mitochondrial Proteinmentioning

confidence: 99%

“…Total iron levels were not altered, yet a fourfold decrease of iron incorporation in heme was found after silencing slc25a39 (Nilsson et al, 2009). Although iron metabolism seems to be affected, it is unlikely that SLC25A39 is necessary to transport iron (Nilsson et al, 2009;Park et al, 2013). Hence, functional annotation in genetic model systems is critical to gain a better understanding of the function of this protein.…”

Section: Introductionmentioning

confidence: 99%

“…Mitochondrial carriers of the SLC25 family bridge biochemical pathways between the cytosol and the mitochondrial matrix (Palmieri, 2014). Members of this family consist of three mitochondrial carrier domains that each contain two hydrophobic stretches that span the membrane as ␣ helices (Saraste and Walker, 1982;Pebay-Peyroula et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

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Shawn, theDrosophilaHomolog of SLC25A39/40, Is a Mitochondrial Carrier That Promotes Neuronal Survival

et al. 2016

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Mitochondria play an important role in the regulation of neurotransmission, and mitochondrial impairment is a key event in neurodegeneration. Cells rely on mitochondrial carrier proteins of the SLC25 family to shuttle ions, cofactors, and metabolites necessary for enzymatic reactions. Mutations in these carriers often result in rare but severe pathologies in the brain, and some of the genes, including SLC25A39 and SLC25A40, reside in susceptibility loci of severe forms of epilepsy. However, the role of most of these carriers has not been investigated in neurons in vivo. We identified shawn, the Drosophila homolog of SLC25A39 and SLC25A40, in a genetic screen to identify genes involved in neuronal function. Shawn localizes to mitochondria, and missense mutations result in an accumulation of reactive oxygen species, mitochondrial dysfunction, and neurodegeneration. Shawn regulates metal homeostasis, and we found in shawn mutants increased levels of manganese, calcium, and mitochondrial free iron. Mitochondrial mutants often cannot maintain synaptic transmission under demanding conditions, but shawn mutants do, and they also do not display endocytic defects. In contrast, shawn mutants harbor a significant increase in neurotransmitter release. Our work provides the first functional annotation of these essential mitochondrial carriers in the nervous system, and the results suggest that metal imbalances and mitochondrial dysfunction may contribute to defects in synaptic transmission and neuronal survival.

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“…a tripartite structure consisting of three tandemly repeated homologous domains of about 100 amino acids in length, each of which contains a distinct signature motif and two hydrophobic stretches that span the membrane as ␣-helices (for reviews see Refs. [3][4][5]. S. cerevisiae possesses 35 members of this family, one of which is localized in peroxisomes and not in mitochondria.…”

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confidence: 99%

Identification and Functional Characterization of a Novel Mitochondrial Carrier for Citrate and Oxoglutarate in Saccharomyces cerevisiae

Castegna

Scarcia

Agrimi

et al. 2010

Journal of Biological Chemistry

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Mitochondrial carriers are a family of transport proteins that shuttle metabolites, nucleotides, and coenzymes across the mitochondrial membrane. The function of only a few of the 35 Saccharomyces cerevisiae mitochondrial carriers still remains to be uncovered. In this study, we have functionally defined and characterized the S. cerevisiae mitochondrial carrier Yhm2p. The YHM2 gene was overexpressed in S. cerevisiae, and its product was purified and reconstituted into liposomes. Its transport properties, kinetic parameters, and targeting to mitochondria show that Yhm2p is a mitochondrial transporter for citrate and oxoglutarate. Reconstituted Yhm2p also transported oxaloacetate, succinate, and fumarate to a lesser extent, but virtually not malate and isocitrate. Yhm2p catalyzed only a counter-exchange transport that was saturable and inhibited by sulfhydrylblocking reagents but not by 1,2,3-benzenetricarboxylate (a powerful inhibitor of the citrate/malate carrier). The physiological role of Yhm2p is to increase the NADPH reducing power in the cytosol (required for biosynthetic and antioxidant reactions) and probably to act as a key component of the citrate-oxoglutarate NADPH redox shuttle between mitochondria and cytosol. This protein function is based on observations documenting a decrease in the NADPH/NADP ؉ and GSH/GSSG ratios in the cytosol of ⌬YHM2 cells as well as an increase in the NADPH/ NADP ؉ ratio in their mitochondria compared with wild-type cells. Our proposal is also supported by the growth defect displayed by the ⌬YHM2 strain and more so by the ⌬YHM2⌬ZWF1 strain upon H 2 O 2 exposure, implying that Yhm2p has an antioxidant function.Yhm2p is a protein of unknown function that has been found to be present in the inner mitochondrial membrane of Saccharomyces cerevisiae (1). This protein was shown to complement the growth defect displayed at 37°C by S. cerevisiae cells lacking ABF2, which encodes a mitochondrial DNA-binding protein involved in mitochondrial DNA replication and recombination (1, 2). In addition, the primary structure of Yhm2p exhibits all the characteristic features of the mitochondrial carrier (MC) 3 protein family, i.e. a tripartite structure consisting of three tandemly repeated homologous domains of about 100 amino acids in length, each of which contains a distinct signature motif and two hydrophobic stretches that span the membrane as ␣-helices (for reviews see Refs. 3-5). S. cerevisiae possesses 35 members of this family, one of which is localized in peroxisomes and not in mitochondria. The majority of yeast MCs has been functionally characterized and shown to transport specific metabolites, nucleotides, and coenzymes across the mitochondrial membrane (for review see Ref. 6). By contrast, the substrate(s) transported by Yhm2p have not yet been discovered, and its physiological function is yet unknown.In this study, we provide evidence that the gene product of YMR241w, named Coc1p and known as Yhm2p, is a citrateoxoglutarate carrier in S. cerevisiae. Yhm2p was overexpressed in S....

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Structure and function of mitochondrial carriers – Role of the transmembrane helix P and G residues in the gating and transport mechanism

Cited by 116 publications

References 51 publications

The mitochondrial phosphate carrier: Role in oxidative metabolism, calcium handling and mitochondrial disease

The mitochondrial phosphate carrier: Role in oxidative metabolism, calcium handling and mitochondrial disease

Shawn, theDrosophilaHomolog of SLC25A39/40, Is a Mitochondrial Carrier That Promotes Neuronal Survival

Identification and Functional Characterization of a Novel Mitochondrial Carrier for Citrate and Oxoglutarate in Saccharomyces cerevisiae

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