Uptake of oxidized folates by rat liver mitochondria

Cybulski, Raymond L.; Fisher, Ronald R.

doi:10.1016/0005-2736(81)90339-4

Cited by 40 publications

(19 citation statements)

References 22 publications

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“…However, the inability to oxidize the methyleneTHF to formylTHF due to lack of the D* and C* activities prevents regeneration of the THF required to maintain the production of glycine from serine and explains the glycine auxotrophy of these cells. Both methyleneTHF from the conversion of serine to glycine, and that produced from the glycine cleavage pathway would act as an intramitochondrial "methylene trap" since folates do not exit to the cytoplasm to a significant extent (31)(32)(33)(34). Although the cell lines used in this study incorporate [1-14 C]glycine and [2-14 C]glycine equally into DNA, indicating that neither cell line carries out significant glycine cleavage activity, this defect could be very significant in tissues that require the pathway in vivo.…”

Section: Discussionmentioning

confidence: 99%

Mammalian Fibroblasts Lacking Mitochondrial NAD+-dependent Methylenetetrahydrofolate Dehydrogenase-Cyclohydrolase Are Glycine Auxotrophs

Patel¹,

Pietro²,

MacKenzie

2003

Journal of Biological Chemistry

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Primary fibroblasts established from embryos of NAD-dependent mitochondrial methylenetetrahydrofolate dehydrogenase-cyclohydrolase (NMDMC) knockout mice were spontaneously immortalized or transformed with SV40 Large T antigen. Mitotracker Red CMXRos staining of the cells indicates the presence of intact mitochondria with a membrane potential. The nmdmc(-/-) cells are auxotrophic for glycine, demonstrating that NMDMC is the only methylenetetrahydrofolate dehydrogenase normally expressed in the mitochondria of these cell lines. Growth of null mutant but not wild type cells on complete medium with dialyzed serum is stimulated about 2-fold by added formate or hypoxanthine. Radiolabeling experiments demonstrated a 3-10 x enhanced incorporation of radioactivity into DNA from formate relative to serine by nmdmc(-/-) cells. The generation of one-carbon units by mitochondria in nmdmc(-/-) cells is completely blocked, and the cytoplasmic folate pathways alone are insufficient for optimal purine synthesis. The results demonstrate a metabolic role for NMDMC in supporting purine biosynthesis. Despite the recognition of these metabolic defects in the mutant cell lines, the phenotype of nmdmc(-/-) embryos that begin to die at E13.5 is not improved when pregnant dams are given a glycine-rich diet or daily injections of sodium formate.

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Section: Discussionmentioning

confidence: 99%

Mammalian Fibroblasts Lacking Mitochondrial NAD+-dependent Methylenetetrahydrofolate Dehydrogenase-Cyclohydrolase Are Glycine Auxotrophs

Patel¹,

Pietro²,

MacKenzie

2003

Journal of Biological Chemistry

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“…a-Serine labeling represents the total SHMT activity of the cell (mitochondrial plus cytoplasmic), whereas label introduced into the b position of serine derives exclusively from mitochondrial SHMT. This is due to the mitochondrial localization of the glycine cleavage complex (Motokawa and Kikuchi, 1971;Ogur et al, 1977) and the inability of reduced folate derivatives to penetrate the mitochondrial membrane to any significant extent (Cybulski and Fisher, 1981;Barlowe and Appling, 1988;Horne et al, 1989;Li et al, 2000). Starting with [2- C]serine in the reaction catalyzed by mitochondrial SHMT.…”

Section: C]glycinementioning

confidence: 96%

A General Method for Determining the Contribution of Split Pathways in Metabolite Production in the Yeast Saccharomyces cerevisiae

Woldman

Appling

2002

Metabolic Engineering

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“…(7,9) Fully reduced substituted folates have not been observed to exchange between the mitochondrial and cytoplasmic compartments. (6,7,10) Therefore, transfer of one-carbon units between these compart- ments must be mediated by the one-carbon donors serine, glycine and formate. (11)(12)(13) In eukaryotes, the enzymes involved in one-carbon folate reactions are often duplicated in compartments defined by the cytoplasm and specific organelles.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial one‐carbon metabolism is adapted to the specific needs of yeast, plants and mammals

2006

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In eukaryotes, folate metabolism is compartmentalized between the cytoplasm and organelles. The folate pathways of mitochondria are adapted to serve the metabolism of the organism. In yeast, mitochondria support cytoplasmic purine synthesis through the generation of formate. This pathway is important but not essential for survival, consistent with the flexibility of yeast metabolism. In plants, the mitochondrial pathways support photorespiration by generating serine from glycine. This pathway is essential under photosynthetic conditions and the enzyme expression varies with photosynthetic activity. In mammals, the expression of the mitochondrial enzymes varies in tissues and during development. In embryos, mitochondria supply formate and glycine for purine synthesis, a process essential for survival; in adult tissues, flux through mitochondria can favor serine production. The differences in the folate pathways of mitochondria depending on species, tissues and developmental stages, profoundly alter the nature of their metabolic contribution.

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Uptake of oxidized folates by rat liver mitochondria

Cited by 40 publications

References 22 publications

Mammalian Fibroblasts Lacking Mitochondrial NAD+-dependent Methylenetetrahydrofolate Dehydrogenase-Cyclohydrolase Are Glycine Auxotrophs

Mammalian Fibroblasts Lacking Mitochondrial NAD+-dependent Methylenetetrahydrofolate Dehydrogenase-Cyclohydrolase Are Glycine Auxotrophs

A General Method for Determining the Contribution of Split Pathways in Metabolite Production in the Yeast Saccharomyces cerevisiae

Mitochondrial one‐carbon metabolism is adapted to the specific needs of yeast, plants and mammals

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