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At least 19 recordsLinked to original sources
PubMed2001

Characterization of a novel human putative mitochondrial transporter homologous to the yeast mitochondrial RNA splicing proteins 3 and 4.

We report here a novel human gene, hMRS3/4, encoding a putative mitochondrial transporter structurally and functionally homologous to the yeast mitochondrial RNA splicing proteins 3 and 4. These proteins belong to the family of mitochondrial carrier proteins (MCF) and are likely to function as solute carriers. hMRS3/4 spans approximately 10 kb of genomic DNA on chromosome 10q24 and consists of four exons that encode a 364-aa protein with six transmembrane domains. A putative splice variant, encoding a 177-aa protein with three transmembrane domains, was also identified. hMRS3/4 has a well-conserved signature sequence of MCF and is targeted into the mitochondria. When expressed in yeast, hMRS3/4 efficiently restores the mitochondrial functions in mrs3(o)mrs4(o) knock-out mutants. Ubiquitous expression in human tissues and a well-conserved structure and function suggest an important role for hMRS3/4 in human cells.

Alternative Splicing↗
PubMed2004

Axonal mitochondrial transport and potential are correlated.

Disruption of axonal transport leads to a disorganized distribution of mitochondria and other organelles and is thought to be responsible for some types of neuronal disease. The reason for bidirectional transport of mitochondria is unknown. We have developed and applied a set of statistical methods and found that axonal mitochondria are uniformly distributed. Analysis of fast axonal transport showed that the uniform distribution arose from the clustering of the stopping events of fast axonal transport in the middle of the gaps between stationary mitochondria. To test whether transport was correlated with ATP production, we added metabolic inhibitors locally by micropipette. Whereas applying CCCP (a mitochondrial uncoupler) blocked mitochondrial transport, as has been previously reported, treatment with antimycin (an inhibitor of electron transport at complex III) caused increases in retrograde mitochondrial transport. Application of 2-deoxyglucose did not decrease transport compared with the mannitol control. To determine whether mitochondrial transport was correlated with mitochondrial potential, we stained the neurons with the mitochondrial potential-sensing dye JC-1. We found that approximately 90% of mitochondria with high potential were transported towards the growth cone and approximately 80% of mitochondria with low potential were transported towards the cell body. These experiments show for the first time that a uniform mitochondrial distribution is generated by local regulation of the stopping events of fast mitochondrial transport, and that the direction of mitochondrial transport is correlated with mitochondrial potential. These results have implications for axonal clogging, autophagy, apoptosis and Alzheimer's disease.

Adenosine Triphosphate↗
PubMed2003

Characteristics of intermittent mitochondrial transport in guinea pig enteric nerve fibers.

Enteric neurons controlling various gut functions are prone to oxidative insults that might damage mitochondria (e.g., intestinal inflammation). To resume local energy supply, mitochondria need to be transported. We used MitoTracker dyes and confocal microscopy to investigate basic characteristics of mitochondrial transport in guinea pig myenteric neurites. During a 10-s observation of 1 mm nerve fiber, on average, three mitochondria were transported at an average speed of 0.41 +/- 0.02 microm/s. Movement patterns were clearly erratic, and velocities were independent of mitochondrial size. The velocity oscillated periodically ( approximately 6 s) but was not consistently affected by structures such as en route boutons, bifurcations, or stationary mitochondria. Also, mitochondria transported in opposite directions did not necessarily affect each others' mobility. Transport was blocked by microtubule disruption (100 microM colchicine), and destabilization (1 microM cytochalasin-D) or stabilization (10 microM phalloidin) of actin filaments, respectively, decreased (0.22 +/- 0.02 microm/s, P < 0.05) or increased (0.53 +/- 0.02 microm/s, P < 0.05) transport speed. Transport was inhibited by TTX (1 microM), and removal of extracellular Ca(2+) (plus 2 mM EGTA) had no effect. However, depletion of intracellular stores (thapsigargin) reduced (to 33%) and slowed the transport significantly (0.18 +/- 0.02 microm/s, P < 0.05), suggesting an important role for stored Ca(2+) in mitochondrial transport. Transport was also reduced (to 21%) by the mitochondrial uncoupler FCCP (1 microM) in a time-dependent fashion and slowed by oligomycin (10 microM). We conclude that mitochondrial transport is remarkably independent of structural nerve fiber properties. We also show that mitochondrial transport is TTX sensitive and speeds up by stabilizing actin and that functional Ca(2+) stores are required for efficient transport.

Actins↗
PubMed1997

Bacterial overexpression of putative yeast mitochondrial transport proteins.

Thirty-two genes have been identified within the genome of the yeast Saccharomyces cerevisiae which putatively encode mitochondrial transport proteins. We have attempted to overexpress a subset of these genes, namely those which encode mitochondrial transporters of unknown function, and have succeeded in overexpressing 19 of these genes. The overexpressed proteins were then isolated and tested for five well-characterized reconstituted transport activities (i.e., the transport of citrate, dicarboxylates, pyruvate, camitine, and aspartate). Utilizing this approach, we have clearly identified the yeast mitochondrial dicarboxylate transport protein, as well as two additional lower-magnitude transport functions (i.e., tricarboxylate and dicarboxylate transport activities). The implications of these results and the considerations relevant to this approach are discussed.

Carrier Proteins↗
PubMed1996

Structural dimorphism in the mitochondrial targeting sequence in the human manganese superoxide dismutase gene. A predictive evidence for conformational change to influence mitochondrial transport and a study of allelic association in Parkinson's disease.

Mitochondrial targeting sequence (MTS) has a common property to form an amphiphilic helical structure which is essential for its effective transport of mitochondrial protein. Natural polymorphism in human MTS which affects its mitochondrial transport ability has not been reported. Furthermore, no structural polymorphism for manganese superoxide dismutase (MnSOD) gene has been studied in human population. We here identify diallelic polymorphism (Ala-9Val) in the MTS of human MnSOD in a Japanese population. Calculation of a helix forming potential predicted the typical amphiphilic helical structure in -9Ala allele and its disruption in -9Val allele. We here suggest that this mutation may reflect functional polymorphism of mitochondrial transport of human MnSOD. An association study using this polymorphism showed significant allelic deviation for -9Ala allele (12.1% vs. 19.3%) in Parkinson's disease.

Aged↗
PubMed2002

Characterization of a putative murine mitochondrial transporter homology of hMRS3/4.

We report here a novel murine gene, Mrs3/4, encoding a putative mitochondrial transporter homologous to the yeast mitochondrial RNA splicing protein 3 and 4 (yMRS3&4) and its human counterpart hMRS3/4. By analyses of radiation hybrids, Mrs3/4 was mapped to mouse Chromosome (Chr) 19 between D19Mit66 and D19Mit24 with a distance of 22.4 cR to D19Mit66, a region that is syntenic to human Chromosome 10q24, where the human gene is located. Structural analysis shows that these proteins belong to the mitochondrial carrier family (MCF), which is characterized by three repeats with two transmembrane domains in each repeat. The murine Mrs3/4 gene has two splicing forms similar to the human homolog. The long form corresponds to the 341-amino acid (aa) protein with six transmembrane domains, and the short form corresponds to the 177-aa protein with three transmembrane domains. Both forms have well-conserved signature sequences of MCF. Targeting experiments showed that both forms have mitochondrial localization. Northern blot analyses showed that Mrs3/4 is ubiquitously expressed as a 1.8-kb transcript with a relative abundance in the heart, liver, kidney, and testis. In conclusion, the reported Mrs3/4 gene shows a strong conservation, mitochondrial protein localization, and a ubiquitous expression, which suggests that it has an important role in mammalian cells, most likely as an ion transporter across the mitochondrial inner membrane.

Amino Acid Sequence↗
PubMed2004

Role of Unc104/KIF1-related motor proteins in mitochondrial transport in Neurospora crassa.

Eukaryotic cells use diverse cytoskeleton-dependent machineries to control inheritance and intracellular positioning of mitochondria. In particular, microtubules play a major role in mitochondrial motility in the filamentous fungus Neurospora crassa and in mammalian cells. We examined the role of two novel Unc104/KIF1-related members of the kinesin family, Nkin2 and Nkin3, in mitochondrial motility in Neurospora. The Nkin2 protein is required for mitochondrial interactions with microtubules in vitro. Mutant hyphae lacking Nkin2 show mitochondrial motility defects in vivo early after germination of conidiospores. Nkin3, a member of a unique fungal-specific subgroup of small Unc104/KIF1-related proteins, is not associated with mitochondria in wild-type cells. However, it is highly expressed and recruited to mitochondria in Deltankin-2 mutants. Mitochondria lacking Nkin2 require Nkin3 for binding to microtubules in vitro, and mitochondrial motility defects in Deltankin-2 mutants disappear with up-regulation of Nkin3 in vivo. We propose that mitochondrial transport is mediated by Nkin2 in Neurospora, and organelle motility defects in Deltankin-2 mutants are rescued by Nkin3. Apparently, a highly versatile complement of organelle motors allows the cell to efficiently respond to exogenous challenges, a process that might also account for the great variety of different mitochondrial transport systems that have evolved in eukaryotic cells.

Animals↗
PubMed2000

The yeast mitochondrial transport proteins: new sequences and consensus residues, lack of direct relation between consensus residues and transmembrane helices, expression patterns of the transport protein genes, and protein-protein interactions with other proteins.

Mitochondrial transport proteins (MTP) typically are homodimeric with a 30-kDa subunit with six transmembrane helices. The subunit possesses a sequence motif highly similar to Pro X Asp/Glu X X Lys/Arg X Arg within each of its three similar 10-kDa segments. Four (YNL083W, YFR045W, YPR021C, YDR470C) of the 35 yeast (S. cerevisiae) MTP genes were resequenced since the masses of their proteins deviate significantly from the typical 30 kDa. We now find these four proteins to have 545, 285, 902, and 502 residues, respectively. Together with only four other MTPs, the sequences of YPR021C and YDR470C show substitutions of some of the five residues that are absolutely conserved among the 12 MTPs with identified transport function and 17 other MTPs. We do now find these five consensus residues also in the new sequences of YNL083W and YFR045W. Additional analyses of the 35 yeast MTPs show that the location of transmembrane helix sequences do not correlate with the general consensus residues of the MTP family; protein segments connecting the six transmembrane helices and facing the intermembrane space are not uniformly short (about 20 residues) or long (about 40 residues) when facing the matrix; most MTPs have at least one transmembrane helix for which the sum of the negative hydropathy values of all residues yields a very small negative value, suggesting a membrane location bordering polar faces of other transmembrane helices or a non-transmembrane location. The extra residues of the three large MTPs are hydrophilic and at the N-terminal. The 200-residue N-terminal segment of YNL083W has four putative Ca2+-binding sites. The 500-residue N-terminal segment of YPR021C shows sequence similarity to enzymes of nucleic acid metabolism. cDNA microarray data show that YNL083W is expressed solely during sporulation, while the expressions of YFR045W, YPR021C, and YDR470C are induced by various stress situations. These results also show that the 35 MTP genes are expressed under a rather diverse set of metabolic conditions that may help identify the function of the proteins. Interestingly, yeast two-hybrid screens, that will also be useful in identifying the function of MTPs, indicate that MIR1, AAC3, YOR100C, and YPR011C do interact with non-MTPs.

Amino Acid Sequence↗
PubMed2005

The human mitochondrial transport protein family: identification and protein regions significant for transport function and substrate specificity.

Protein sequence similarities and predicted structures identified 75 mitochondrial transport proteins (37 subfamilies) from among the 28,994 human RefSeq (NCBI) protein sequences. All, except two, have an E-value of less than 4e--05 with respect to the structure of the single subunit bovine ADP/ATP carrier/carboxyatractyloside complex (bAAC/CAT) (mGenThreader program). The two 30-kDa exceptions have E-values of 0.003 and 0.005. 21 have been functionally identified and belong to 14 subfamilies. A subset of subfamilies with sequence similarities for each of 12 different protein regions was identified. Many of the 12 protein regions for each tested protein yielded different size subsets. The sum of subfamilies in the 12 subsets was lowest for the phosphate transport protein (PTP) and highest for aralar 1. Transmembrane sequences are most unique. Sequence similarities are highest near the membrane center and matrix. They are highest for the region of transmembrane helices H1, H2 and connecting matrix loop 12 and smallest for transmembrane helices H3, H4 and loop 34. These sequence similarities and the predicted high similarities to the bAAC/CAT structure point to common structural/functional elements that could include subunit/subunit contact sites as they have been identified for PTP and AAC. The four residues protein segment (SerLysGlnIle) of loop 12 is the only segment projecting into the center of the funnel-like structure of the bAAC/CAT. It is present in its entirety only in the AACs and with some replacements in the large Ca2+-modulated aspartate/glutamate transporters. Other transporters have deletions and replacements in this region of loop 12. This protein segment with its central location and variation in size and composition likely contributes to the substrate specificity of the transporters.

Amino Acid Sequence↗
PubMed1980

[Mechanisms of disruption of mitochondrial transport of adenine nucleotides in the course of acute hepatic ischemia].

Suppression of mitochondrial transport of adenine nucleotides (AN) in the ischemized liver is caused by inhibition of adenine nucleotide translocase by long chain acyl-KoA and by reduced exchange fund of intramitochondrial AN. It preceeds the disunion of oxidizing phosphorylation which develops during the period of marked structural disturbances of the mitochondrial membrane. The preincubation of mitochondria from the ischemized liver with carnitine and alpha-ketoglutarate stimulates breathing in the metabolic state. The ischemic toxin blocking SH-groups of the membrane proteins also inhibits the transport of AN. However, its effect on the mitochondrial membrane is dominated by the disintegrating component.

Acute Disease↗
PubMed2026

The insulin-like growth factor 2 mRNA-binding protein 2 affects tumor cell metabolism via mitochondrial transporter activity and lipid alterations.

The insulin-like growth factor 2 mRNA-binding protein (IGF2BP) family is overexpressed in cancer and associated with poor prognosis. IGF2BP2 has been linked to single metabolic alterations by acting on its RNA targets. Here, we used a comprehensive approach to elucidate the effects of IGF2BP2 on primary and lipid metabolism. 13C-metabolic flux analysis (MFA) combined with RNA-Seq data revealed that IGF2BP2 affects mitochondrial fluxes by regulating the expression of several mitochondrial transporters, such as mitochondrial pyruvate carrier 1 (MPC1) and uncoupling protein 2 (UCP2). Methyl pyruvate reversed the gene expression patterns of UCP2 and CPT1A in HCT116 IGF2BP2 knockout (KO) cells by bypassing MPC1. Interestingly, an altered expression of the transporter UCP2 was also observed in a patient-derived tumor organoid (PDO), in which IGF2BP2 was knocked down. The altered glutamine metabolism seen in the 13C-MFA and the citrate label data derived from extracted mitochondria confirm a rerouting of glutamine almost exclusively into the mitochondria and a reduction of glycolytic carbon intake into the mitochondria. Due to changes in palmitate labeling patterns, lipid stainings were performed, suggesting lipid accumulation in KO cells. A lipidomic analysis revealed altered compositions across almost all lipid species. Further, lipogenic genes involved in fatty acid and cholesterol metabolism were differentially expressed. Most of the differentially expressed genes are potential direct targets of IGF2BP2 based on publicly available IGF2BP2 CLIP data. Overall, these results show the influence of IGF2BP2 on the central carbon metabolism of cancer cells, primarily through its effects on MPC1 and the resulting effects on UCP2. The complex interaction of IGF2BP2 with the metabolic network provides important insights into tumor metabolism, particularly relevant to tumor growth and resistance to therapy.

Journal Article↗
PubMed1999

Mitochondrial transport of cations: channels, exchangers, and permeability transition.

This review provides a selective history of how studies of mitochondrial cation transport (K+, Na+, Ca2+) developed in relation to the major themes of research in bioenergetics. It then covers in some detail specific transport pathways for these cations, and it introduces and discusses open problems about their nature and physiological function, particularly in relation to volume regulation and Ca2+ homeostasis. The review should provide the basic elements needed to understand both earlier mitochondrial literature and current problems associated with mitochondrial transport of cations and hopefully will foster new interest in the molecular definition of mitochondrial cation channels and exchangers as well as their roles in cell physiology.

Animals↗
PubMed1984

Effect of mutants and inhibitors on mitochondrial transport systems in vivo in yeast.

We have reported elsewhere (Wills, C. and Martin, T. (1984) Biochim. Biophys. Acta 782, 274-284) that one or more mitochondrial transport systems may be involved in the regulation of the inducible alcohol dehydrogenase of yeast, ADH-II. In order to investigate this phenomenon further, it was necessary to determine which of these systems operate in the cell in vivo. We give in this paper preliminary evidence that inhibitors of the malate-phosphate (n-butyl malonate), malate-citrate (hydroxycitrate) and malate-alpha-ketoglutarate (aminooxyacetate or cycloserine) transport systems all operate in vivo. While the demonstration of the in vivo inhibitory activity of n-butyl malonate and hydroxycitrate is entirely by physiological methods, that of the transaminase inhibitors aminooxyacetate and cycloserine depends in part on the isolation of mutants capable of growth on glycerol in minimal medium. On this medium these mutants depend on the malate-aspartate shuttle for growth, and as expected the transaminase inhibitors prevent their growth. Two of the mutants show an enhanced rate of mitochondrial glutamate uptake. A preliminary survey of the properties of the glycerol growth mutants is presented, showing that the probable mode of action of these mutants is an increase in the efficiency of the malate-aspartate shuttle.

Alcohol Dehydrogenase↗
PubMed2007

Altered axonal mitochondrial transport in the pathogenesis of Charcot-Marie-Tooth disease from mitofusin 2 mutations.

Mutations in the mitochondrial fusion protein mitofusin 2 (MFN2) are the most commonly identified cause of Charcot-Marie-Tooth type 2 (CMT2), a dominantly inherited disease characterized by degeneration of peripheral sensory and motor axons. However, the mechanism by which mutations in this ubiquitously expressed mitochondrial fusion protein lead to neuropathy has not yet been elucidated. To explore how MFN2 mutations lead to degeneration of peripheral axons, we expressed neuropathy-associated forms of MFN2 in cultured dorsal root ganglion neurons, cells preferentially affected in CMT2. Disease-associated MFN2 mutant proteins induced abnormal clustering of small fragmented mitochondria in both neuronal cell bodies and proximal axons. Interestingly, transport of mitochondria in axons was significantly impaired in neurons expressing disease-mutated forms of MFN2. The diminished axonal mitochondrial transport was not attributable to diminished ATP levels in the neurons, and oxidative respiration was normal in mutant MFN2-expressing cells. Additionally, mitochondrial oxidative enzyme activity was normal in muscle mitochondria from a CMT2 patient with an MFN2 mutation, further supporting that abnormal mitochondrial transport in neurons is independent from an energy production defect. This abnormal mitochondrial trafficking provides a likely explanation for the selective susceptibility of the longest peripheral axons to MFN2 mutations, in which proper localization of mitochondria is critical for axonal and synaptic function.

Animals↗
PubMed2006

Heme oxygenase-1 enhances renal mitochondrial transport carriers and cytochrome C oxidase activity in experimental diabetes.

Up-regulation of heme oxygenase (HO-1) by either cobalt protoporphyrin (CoPP) or human gene transfer improves vascular and renal function by several mechanisms, including increases in antioxidant levels and decreases in reactive oxygen species (ROS) in vascular and renal tissue. The purpose of the present study was to determine the effect of HO-1 overexpression on mitochondrial transporters, cytochrome c oxidase, and anti-apoptotic proteins in diabetic rats (streptozotocin, (STZ)-induced type 1 diabetes). Renal mitochondrial carnitine, deoxynucleotide, and ADP/ATP carriers were significantly reduced in diabetic compared with nondiabetic rats (p < 0.05). The citrate carrier was not significantly decreased in diabetic tissue. CoPP administration produced a robust increase in carnitine, citrate, deoxynucleotide, dicarboxylate, and ADP/ATP carriers and no significant change in oxoglutarate and aspartate/glutamate carriers. The increase in mitochondrial carriers (MCs) was associated with a significant increase in cytochrome c oxidase activity. The administration of tin mesoporphyrin (SnMP), an inhibitor of HO-1 activity, prevented the restoration of MCs in diabetic rats. Human HO-1 cDNA transfer into diabetic rats increased both HO-1 protein and activity, and restored mitochondrial ADP/ATP and deoxynucleotide carriers. The increase in HO-1 by CoPP administration was associated with a significant increase in the phosphorylation of AKT and levels of BcL-XL proteins. These observations in experimental diabetes suggest that the cytoprotective mechanism of HO-1 against oxidative stress involves an increase in the levels of MCs and anti-apoptotic proteins as well as in cytochrome c oxidase activity.

Animals↗
PubMed1996

High-level bacterial expression of mitochondrial transport proteins.

The inability to obtain abundant quantities of purified, functional membrane proteins has represented a significant impediment to the goal of obtaining high-resolution structural information. In this review, procedures are described which have been developed in this laboratory and enable the high-level bacterial expression and subsequent purification of functional mitochondrial citrate transport proteins from yeast and rat liver. The data that we have obtained using these procedures and related results from other laboratories are discussed. Additionally, the general applicability of this approach to most mitochondrial transport proteins as well as to other types of membrane proteins is considered. Finally, relevant considerations when contemplating the use of this methodology and the likely value of this approach in future areas of research are explored.

Animals↗
PubMed1993

Mitochondrial transport of mitoribosomal proteins, YmL8 and YmL20, in Saccharomyces cerevisiae.

Two mitochondrial ribosomal (mitoribosomal) proteins, YmL8 and YmL20, of the yeast Saccharomyces cerevisiae and their derivatives were synthesized in vitro and their transport into isolated yeast mitochondria was examined. Of the two proteins, YmL20 possesses an N-terminal presequence of 18 amino acid residues, while YmL8 has no such presequence. Both proteins were found to be transported into isolated mitochondria in an energy-dependent manner. Furthermore, YmL20 protein without its N-terminal presequence was also transported, despite the fact that the presequence alone was capable of transporting a fused passenger protein, Chinese hamster dihydrofolate reductase (DHFR). Therefore, YmL20 protein appears to possess redundant transport signals in its structure. Similarly, YmL8 derivatives lacking either 40 or 86 amino acid residues from the N-terminus and/or 52 amino acid residues from the C-terminus were transported. In addition, the N-terminal segment of this protein was capable of transporting Chinese hamster DHFR into mitochondria, while its C-terminal segment was not. Thus, YmL8 protein also appears to possess two or more transport signals in its structure. Perhaps the presence of many basic amino acid residues in these proteins might, at least partly, contribute to their mitochondrial transport.

Animals↗