SHM1: A multicopy suppressor of a temperature-sensitive null mutation in the HMG1-likeabf2 gene

Kao, Li Cheng; Megraw, Timothy L.; Chae, Chi‐Bom

doi:10.1002/(sici)1097-0061(19960930)12:12<1239::aid-yea17>3.0.co;2-8

Cited by 26 publications

(30 citation statements)

References 36 publications

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“…Of all of the mutants tested, only one mutation, corresponding to a previously uncharacterized ORF YGR257c, reproducibly showed a consistent strong loss of SOD2 activity (Table 1). Some loss of SOD2 activity was also observed with mutations in YDL198c (YHM1) (27) and YPL270w (MDL2) (28); however, the effects were quite small ( Table 1). The strong SOD2 defect associated with the commercially available YGR257c mutant was reproduced in a ygr257c⌬::LEU2 mutant strain that we had engineered.…”

Section: An Mcf Protein Is Required For Manganese Activation Of Sod2 mentioning

confidence: 96%

Manganese activation of superoxide dismutase 2 in Saccharomyces cerevisiae requires MTM1 , a member of the mitochondrial carrier family

Luk

Carroll

Baker

et al. 2003

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

138

149

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Manganese-containing superoxide dismutase (SOD2) plays a critical role in guarding against mitochondrial oxidative stress and is essential for survival of many organisms. Despite the recognized importance of SOD2, nothing is known regarding the mechanisms by which this nuclear-encoded protein is converted to an active enzyme in the mitochondrial matrix. To search for factors that participate in the posttranslational activation of SOD2, we screened for yeast genes that when mutated lead to SOD2 inactivation and identified a single ORF, YGR257c. The encoded protein localizes to the mitochondria and represents a member of the yeast mitochondrial carrier family. YGR257c was previously recognized as the homologue to human CGI-69, a widely expressed mitochondrial carrier family of unknown function. Our studies suggest a connection with SOD2, and we have named the yeast gene MTM1 for manganese trafficking factor for mitochondrial SOD2. Inactivation of yeast MTM1 leads to loss of SOD2 activity that is restored only when cells are treated with high supplements of manganese, but not other heavy metals, indicative of manganese deficiency in the SOD2 polypeptide. Surprisingly, the mitochondrial organelle of mtm1⌬ mutants shows no deficiency in manganese levels. Moreover, mtm1⌬ mutations do not impair activity of a cytosolic version of manganese SOD. We propose that Mtm1p functions in the mitochondrial activation of SOD2 by specifically facilitating insertion of the essential manganese cofactor.

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Section: An Mcf Protein Is Required For Manganese Activation Of Sod2 mentioning

confidence: 96%

Manganese activation of superoxide dismutase 2 in Saccharomyces cerevisiae requires MTM1 , a member of the mitochondrial carrier family

Luk

Carroll

Baker

et al. 2003

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

138

149

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“…Flx1p, FAD (13); Leu5p, coenzyme A (14)). (iii) Several genes encoding members of the MCF were identified by genetic screens that did not immediately allow any conclusions with respect to their substrates (MRS3 and MRS4 (15); MRS12/RIM2 (16); YHM1/SHM1 (17); YHM2 (18)). (iv) Limited information from systematic studies is available for a few genes encoding predicted mitochondrial carrier proteins (19,20), while (v) nothing is known about the remaining open reading frames.…”

Section: The Genome Of the Yeast Saccharomyces Cerevisiae Contains 35mentioning

confidence: 99%

A Specific Role of the Yeast Mitochondrial Carriers Mrs3/4p in Mitochondrial Iron Acquisition under Iron-limiting Conditions

Mühlenhoff

Stadler

Richhardt

et al. 2003

Journal of Biological Chemistry

179

180

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The yeast genes MRS3 and MRS4 encode two members of the mitochondrial carrier family with high sequence similarity. To elucidate their function we utilized genome-wide expression profiling and found that both deletion and overexpression of MRS3/4 lead to up-regulation of several genes of the "iron regulon." We therefore analyzed the two major iron-utilizing processes, heme formation and Fe/S protein biosynthesis in vivo, in organello (intact mitochondria), and in vitro (mitochondrial extracts). Radiolabeling of yeast cells with 55 Fe revealed a clear correlation between MRS3/4 expression levels and the efficiency of these biosynthetic reactions indicating a role of the carriers in utilization and/or transport of iron in vivo. Similar effects on both heme formation and Fe/S protein biosynthesis were seen in organello using mitochondria isolated from cells grown under iron-limiting conditions. The correlation between MRS3/4 expression levels and the efficiency of the two iron-utilizing processes was lost upon detergent lysis of mitochondria. As no significant changes in the mitochondrial membrane potential were observed upon overexpression or deletion of MRS3/4, our results suggest that Mrs3/4p carriers are directly involved in mitochondrial iron uptake. Mrs3/4p function in mitochondrial iron transport becomes evident under ironlimiting conditions only, indicating that the two carriers do not represent the sole system for mitochondrial iron acquisition. Proteins belonging to the mitochondrial carrier family (MCF)1 form a large group of structurally related proteins, which exist exclusively in eukaryotes (for reviews, see Refs. 1-3). Typical mitochondrial carrier proteins have a molecular mass of about 35 kDa, contain six membrane-spanning segments, and have a tripartite structure. Each of the three parts is made up of about 100 amino acids and shares sequence homology to the other modules of the proteins. Most members of the MCF are integral proteins of the mitochondrial inner membrane and function in the shuttling of various metabolites and cofactors between the cytosol and mitochondria. The substrates of mitochondrial carrier proteins are rather diverse in size and composition, ranging from protons transported by the uncoupling protein up to large molecules such as ATP and ADP exchanged by the ADP/ATP carrier. Other members of this family are responsible for the transport of phosphate, citrate, fumarate/succinate, carnitine/acylcarnitine, flavine adenine dinucleotide (FAD), and other substrates. One member of the MCF has been located in peroxisomes where it was shown to transport ATP in exchange for AMP (4). The genome of the yeast Saccharomyces cerevisiae contains 35 open reading frames that encode members of the MCF (5-7).The genes can be divided into five subclasses. (i) The functions of the encoded proteins are known, and their transport activities were investigated by expression in Escherichia coli and reconstitution of the purified proteins in liposome vesicles (e.g. Mir1p/PiC, phosphate (8); Arg11p/ORC, o...

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“…In an earlier study, YHM1 was identified as a high copy suppressor of mtDNA instability associated with an ABF2 deletion [10], but phenotypic defects associated with iron or GTP metabolism were not reported.…”

Section: Introductionmentioning

confidence: 99%

GTP in the mitochondrial matrix plays a crucial role in organellar iron homoeostasis

Gordon

Lyver

Lesuisse

et al. 2006

Biochemical Journal

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Mitochondria are the major site of cellular iron utilization for the synthesis of essential cofactors such as iron-sulfur clusters and haem. In the present study, we provide evidence that GTP in the mitochondrial matrix is involved in organellar iron homoeostasis. A mutant of yeast Saccharomyces cerevisiae lacking the mitochondrial GTP/GDP carrier protein (Ggc1p) exhibits decreased levels of matrix GTP and increased levels of matrix GDP [Vozza, Blanco, Palmieri and Palmieri (2004) J. Biol. Chem. 279, 20850-20857]. This mutant (previously called yhm1) also manifests high cellular iron uptake and tremendous iron accumulation within mitochondria [Lesuisse, Lyver, Knight and Dancis (2004) Biochem. J. 378, 599-607]. The reason for these two very different phenotypic defects of the same yeast mutant has so far remained elusive. We show that in vivo targeting of a human nucleoside diphosphate kinase (Nm23-H4), which converts ATP into GTP, to the matrix of ggc1 mutants restores normal iron regulation. Thus the role of Ggc1p in iron metabolism is mediated by effects on GTP/GDP levels in the mitochondrial matrix.

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SHM1: A multicopy suppressor of a temperature-sensitive null mutation in the HMG1-likeabf2 gene

Cited by 26 publications

References 36 publications

Manganese activation of superoxide dismutase 2 in Saccharomyces cerevisiae requires MTM1 , a member of the mitochondrial carrier family

Manganese activation of superoxide dismutase 2 in Saccharomyces cerevisiae requires MTM1 , a member of the mitochondrial carrier family

A Specific Role of the Yeast Mitochondrial Carriers Mrs3/4p in Mitochondrial Iron Acquisition under Iron-limiting Conditions

GTP in the mitochondrial matrix plays a crucial role in organellar iron homoeostasis

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