An ABC transporter in the mitochondrial inner membrane is required for normal growth of yeast.

Tpk2, but not Tpk1 or Tpk3, is required for pseudohyphal growth. Genome-wide transcriptional profiling has revealed unique signatures for each of the three A kinases leading to the identification of additional functional diversity among these proteins. Tpk2 negatively regulates genes involved in iron uptake and positively regulates genes involved in trehalose degradation and water homeostasis. Tpk1 is required for the derepression of branched chain amino acid biosynthesis genes that seem to have a second role in the maintenance of iron levels and DNA stability within mitochondria. The fact that TPK2 mutants grow better than wild types on nonfermentable carbon sources and on media deficient in iron supports the unique role of Tpk2 in respiratory growth and carbon source use.I n yeast, cAMP acting through the A kinases (PKA) provides a key regulatory signal for growth on diverse carbon sources. Growth on fermentable carbon sources (e.g., glucose, fructose, and sucrose) requires a higher basal level of cAMP than does growth on nonfermentable carbon sources (e.g., ethanol, glycerol, and acetate). Therefore, the level of cAMP must decrease in order for cells to switch from growth on fermentable carbon sources to growth on nonfermentable carbon sources (the diauxic shift; ref. 1). Addition of glucose to yeast cells growing on a nonfermentable carbon source or starved for glucose results in a transient peak in intracellular cAMP levels. This transition to fermentation requires both the transient increase of cAMP and the cAMP-dependent PKA (2). Activated PKA shifts the metabolic flux away from gluconeogenesis and toward glycolysis by regulating key enzymes in these processes including fructose-1,6-bisphosphatase and phosphofructokinase-2 (3). Phosphorylation by PKA inactivates the transcription factor Adr1, a positive regulatory factor for the transcription of the respiratory enzyme Adh2 (4). In addition, PKA promotes the breakdown of glycogen and trehalose by inhibiting enzymes involved in synthesis (trehalose synthase and glycogen synthase) and activating enzymes involved in breakdown (trehalase and glycogen phosphorylase) of these storage carbohydrates.The transcriptional changes occurring in the transition from fermentative growth to respiratory growth have been monitored by genome expression arrays (5). As glucose is depleted, transcription of genes involved in respiration, the tricarboxylic acid cycle, the glyoxylate cycle, gluconeogenesis, and storage carbohydrate synthesis is induced, whereas transcription of genes involved in glycolysis and protein synthesis is repressed (5). Consistent with the shift to respiratory growth, cytoplasmic ribosomal protein genes are repressed, and mitochondrial ribosomal genes are induced. In view of the role of cAMP and the PKAs in the use of carbon sources, these results raise the question of whether the PKAs function in respiratory growth and whether they are redundant for this function.To elucidate more broadly the functional differences between the PKA catalytic subunits, we ...

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“…Atm1, an ABC transporter required for iron homeostasis, is located in the mitochondrial inner membrane (22).…”

Section: Tpk1 Regulates Genes Of the Branched Chain Amino Acid Pathwamentioning

confidence: 99%

The yeast A kinases differentially regulate iron uptake and respiratory function

Robertson

Causton

Young

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

162

150

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“…Atm1p is classified as a "half-transporter" that functions as a homodimer and is localized in the mitochondrial inner membrane with the ATPase domains at the matrix side (Leighton and Schatz, 1995). The orientation indicates that the direction of transport is from the mitochondrial matrix to the intermembrane space and cytosol.…”

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confidence: 99%

An Allelic Mutant Series of ATM3 Reveals Its Key Role in the Biogenesis of Cytosolic Iron-Sulfur Proteins in Arabidopsis

et al. 2009

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The ATP-binding cassette transporters of mitochondria (ATMs) are highly conserved proteins, but their function in plants is poorly defined. Arabidopsis (Arabidopsis thaliana) has three ATM genes, namely ATM1, ATM2, and ATM3. Using a collection of insertional mutants, we show that only ATM3 has an important function for plant growth. Additional atm3 alleles were identified among sirtinol-resistant lines, correlating with decreased activities of aldehyde oxidases, cytosolic enzymes that convert sirtinol into an auxin analog, and depend on iron-sulfur (Fe-S) and molybdenum cofactor (Moco) as prosthetic groups. In the sirtinol-resistant atm3-3 allele, the highly conserved arginine-612 is replaced by a lysine residue, the negative effect of which could be mimicked in the yeast Atm1p ortholog. Arabidopsis atm3 mutants displayed defects in root growth, chlorophyll content, and seedling establishment. Analyses of selected metal enzymes showed that the activity of cytosolic aconitase (Fe-S) was strongly decreased across the range of atm3 alleles, whereas mitochondrial and plastid Fe-S enzymes were unaffected. Nitrate reductase activity (Moco, heme) was decreased by 50% in the strong atm3 alleles, but catalase activity (heme) was similar to that of the wild type. Strikingly, in contrast to mutants in the yeast and mammalian orthologs, Arabidopsis atm3 mutants did not display a dramatic iron homeostasis defect and did not accumulate iron in mitochondria. Our data suggest that Arabidopsis ATM3 may transport (1) at least two distinct compounds or (2) a single compound required for both Fe-S and Moco assembly machineries in the cytosol, but not iron.

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“…The substrate of yAtm1p has not been clarified, but Leighton and Schatz (1995) proposed that this protein is involved in the transport of heme across the mitochondrial membrane. Yeast ABC protein families have been classified into six major clusters and ten subclusters.…”

Section: Structural Characteristicsmentioning

confidence: 99%

“…By a screening for human homologues using our private database of human expressed-sequence tags (ESTs) (Fujiwara et al unpublished data) against the yeast genomic sequence deposited in GenBank and the European Molecular Biology Laboratory (EMBL, Heidelberg), we obtained an EST homologous to yeast ATM1, an ATP-binding (ABC) transporter gene (Leighton and Schatz 1995) and a partial sequence of the murine ABC7 (mABC7) gene. Recently, the complete sequence of mABC7 was cloned and reported by Savary et al (Savary et al 1997).…”

Section: Introductionmentioning

confidence: 99%

“…The protein yAtm1p is one of only a few members of the mitochondrial ABC transporter family that have been identified; it is essential for normal cellular growth, as disruption of the gene results in a major deficiency of cytochromes in mitochondria and instability of mitochondrial DNA. Thus, yAtm1p is assumed to be a heme transporter (Leighton and Schatz 1995). However, the biochemical functions and substrates of yAtm1p are not yet fully understood.…”

Section: Introductionmentioning

confidence: 99%

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Cloning and chromosomal mapping of a novel ABC transporter gene (hABC7), a candidate for X-linked sideroblastic anemia with spinocerebellar ataxia

et al. 1998

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We isolated a novel human ATP-binding cassette (ABC) transporter cDNA, determined its nucleotide sequence, and designated it human ABC7 (hABC7). The nucleotide sequence was highly homologous to the ATM1 gene in yeast, which encodes an ABC transporter (yAtm1p) located in the mitochondrial inner membrane. The deduced human product, a putative half-type transporter, consists of 752 amino acids that are 48.9% identical to those of yAtm1p. A computer-assisted protein structural and localization analysis revealed that the mitochondrial targeting signal of yAtm1p is conserved in the N-terminal region of the primary sequence of the hABC7 protein, and therefore this product is also likely to be located in the mitochondrial inner membrane. The evidence strongly suggests that the hABC7 gene is a counterpart of ATM1 and that its product is probably involved in heme transport. We mapped the hABC7 gene to chromosome Xq13.1-q13.3 by fluorescence in-situ hybridization. As band Xq13 has been implicated in X-linked sideroblastic anemia with spinocerebellar ataxia, hABC7 becomes a candidate gene for this heritable disorder.

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An ABC transporter in the mitochondrial inner membrane is required for normal growth of yeast.

Cited by 185 publications

References 74 publications

The yeast A kinases differentially regulate iron uptake and respiratory function

The yeast A kinases differentially regulate iron uptake and respiratory function

An Allelic Mutant Series of ATM3 Reveals Its Key Role in the Biogenesis of Cytosolic Iron-Sulfur Proteins in Arabidopsis

Cloning and chromosomal mapping of a novel ABC transporter gene (hABC7), a candidate for X-linked sideroblastic anemia with spinocerebellar ataxia

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