Pyruvate Dehydrogenase Phosphatase Deficiency: Identification of the First Mutation in Two Brothers and Restoration of Activity by Protein Complementation

Maj, Mary C.; MacKay, N.; Levandovskiy, Valeriy; Addis, Jane; Baumgartner, E. R.; Baumgartner, Matthias; Robinson, Brian H.; Cameron, Jessie M.

doi:10.1210/jc.2005-0123

Cited by 61 publications

(51 citation statements)

References 34 publications

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“…Fetal glucose and oxygen consumption converge at the transport of pyruvate into mitochondria; therefore, we targeted Mpc1, an essential component of the mitochondrial pyruvate carrier, to determine the requirements for mitochondrial pyruvate metabolism during fetal development. Due to the severe metabolic and developmental derangements observed in patients with mutations in enzymes that participate in mitochondrial pyruvate metabolism (26,(40)(41)(42)(43)(44) and the embryonic lethality of mouse models with null mutations in these enzymes (21, 45), we were surprised that such a small fraction of mitochondrial pyruvate metabolism was sufficient for in utero development. MPC deficiency was well tolerated in egg-laying Drosophila under standard laboratory conditions; however, these mutations were lethal when carbohydrate (sucrose) was provided as the main macronutrient (12).…”

Section: Discussionmentioning

confidence: 99%

Requirement for the Mitochondrial Pyruvate Carrier in Mammalian Development Revealed by a Hypomorphic Allelic Series

Bowman

Zhao

Hartung

et al. 2016

Molecular and Cellular Biology

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bGlucose and oxygen are two of the most important molecules transferred from mother to fetus during eutherian pregnancy, and the metabolic fates of these nutrients converge at the transport and metabolism of pyruvate in mitochondria. Pyruvate enters the mitochondrial matrix through the mitochondrial pyruvate carrier (MPC), a complex in the inner mitochondrial membrane that consists of two essential components, MPC1 and MPC2. Here, we define the requirement for mitochondrial pyruvate metabolism during development with a progressive allelic series of Mpc1 deficiency in mouse. Mpc1 deletion was homozygous lethal in midgestation, but Mpc1 hypomorphs and tissue-specific deletion of Mpc1 presented as early perinatal lethality. The allelic series demonstrated that graded suppression of MPC resulted in dose-dependent metabolic and transcriptional changes. Steady-state metabolomics analysis of brain and liver from Mpc1 hypomorphic embryos identified compensatory changes in amino acid and lipid metabolism. Flux assays in Mpc1-deficient embryonic fibroblasts also reflected these changes, including a dramatic increase in mitochondrial alanine utilization. The mitochondrial alanine transaminase GPT2 was found to be necessary and sufficient for increased alanine flux upon MPC inhibition. These data show that impaired mitochondrial pyruvate transport results in biosynthetic deficiencies that can be mitigated in part by alternative anaplerotic substrates in utero. E mbryonic development in eutherian mammals is defined by ongoing metabolic interactions between mother and fetus. Placentas have evolved a sophisticated suite of adaptations to ensure adequate nutrient, gas, and waste exchange between fetus and mother, as well as hormonal and immunological communication (1, 2). To meet the fetal requirements for nutrient and oxygen consumption during pregnancy, maternal cardiac output increases such that uteroplacental blood flow accounts for ϳ25% of total cardiac output (3). Glucose and oxygen are arguably the two most important molecules transferred from mother to fetus, in terms of both concentration and the multitude of physiological adaptations in place to ensure their adequate transport; however, the requirement for mitochondrial oxidative metabolism during embryonic development remains poorly defined.While oxygen tension in utero is low relative to atmospheric levels, measurement of oxygen consumption and lactate uptake in fetal lambs provided evidence that the fetus is a net consumer rather than a producer of lactate (4). Consistent with this, fetal myocardium consumes a large amount of lactate, in addition to glucose, indicating that oxidative metabolism of carbohydrates is an important energy source in the developing heart (5, 6). Additionally, lactate utilization is high in the neonatal brain, and the capacity for lactate import is higher in the neonatal brain than in the adult brain (7). Together, these observations provide evidence for the importance of mitochondrial oxidative metabolism early in mammalian development. S...

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Section: Discussionmentioning

confidence: 99%

Requirement for the Mitochondrial Pyruvate Carrier in Mammalian Development Revealed by a Hypomorphic Allelic Series

Bowman

Zhao

Hartung

et al. 2016

Molecular and Cellular Biology

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“…These regulatory enzymes themselves are regulated by a variety of conditions, including the intramitochondrial concentrations of cofactors and substrates or products of PDC reaction (1,3,7,11,(47)(48)(49), indicating a complex multilayer regulatory network. Failure of the human PDC (50) or of one of its regulatory enzymes (51,52) results in serious disorders. In yeast, however, the conversion of pyruvate to acetyl-CoA can be bypassed by two additional mitochondrial and cytoplasmic pathways (53,54).…”

Section: Discussionmentioning

confidence: 99%

Yeast Pyruvate Dehydrogenase Complex Is Regulated by a Concerted Activity of Two Kinases and Two Phosphatases

Gey

Czupalla

Hoflack

et al. 2008

Journal of Biological Chemistry

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The activity of yeast pyruvate dehydrogenase complex is regulated by reversible phosphorylation. Recently we identified two enzymes that are involved in the phosphorylation (Pkp1p) and dephosphorylation (Ppp1p) of Pda1p, the ␣-subunit of the pyruvate dehydrogenase complex. Here we provide evidence that two additional mitochondrial proteins, Pkp2p (Ygl059wp) and Ppp2p (Ycr079wp), are engaged in the regulation of this complex by affecting the phosphorylation state of Pda1p. Our data indicate complementary activities of the kinases and a redundant function for the phosphatases. Both proteins are associated with the complex. We propose a model for the role of the regulatory enzymes and the phosphorylation state of Pda1p in the assembly process of the pyruvate dehydrogenase complex.

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“…These early reports of PDH phosphatase deWciency, based on biochemical enzyme assay, exhibited severe symptoms with fatal lactic acidosis (DeVivo et al 1979;Koster et al 1978;Robinson and Sherwood 1975). We previously identiWed the Wrst molecular diagnosis for patients with PDP1 deWciency, two brothers who had a homozygous three base pair deletion in the PDP1 gene resulting in 25% native PDHc activity (Maj et al 2005). These brothers display exercise intolerance but are successfully being treated with a ketogenic diet.…”

Section: Introductionmentioning

confidence: 99%

Pyruvate dehydrogenase phosphatase 1 (PDP1) null mutation produces a lethal infantile phenotype

et al. 2009

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Pyruvate dehydrogenase phosphatase deficiency has previously only been confirmed at the molecular level in two brothers and two breeds of dog with exercise intolerance. A female patient, who died at 6 months, presented with lactic acidemia in the neonatal period with serum lactate levels ranging from 2.5 to 17 mM. Failure of dichloroacetate to activate the PDH complex in skin fibroblasts was evident, but not in early passages. A homozygous c.277G > T (p.E93X) nonsense mutation in the PDP1 gene was identified in genomic DNA and immunoblotting showed a complete absence of PDP1 protein in mitochondria. Native PDHC activity could be restored by the addition of either recombinant PDP1 or PDP2. This highlights the role of PDP2, the second phosphatase isoform, in PDP1-deficient patients for the first time. We conclude that the severity of the clinical course associated with PDP1 deficiency can be quite variable depending on the exact nature of the molecular defect.

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Pyruvate Dehydrogenase Phosphatase Deficiency: Identification of the First Mutation in Two Brothers and Restoration of Activity by Protein Complementation

Abstract: We have identified mutations in PDP1 in two brothers with PDP deficiency and have proven that the mutation is disease-causing. This is the first demonstration of human disease due to a mutation in PDP1.

Cited by 61 publications

References 34 publications

Requirement for the Mitochondrial Pyruvate Carrier in Mammalian Development Revealed by a Hypomorphic Allelic Series

Requirement for the Mitochondrial Pyruvate Carrier in Mammalian Development Revealed by a Hypomorphic Allelic Series

Yeast Pyruvate Dehydrogenase Complex Is Regulated by a Concerted Activity of Two Kinases and Two Phosphatases

Pyruvate dehydrogenase phosphatase 1 (PDP1) null mutation produces a lethal infantile phenotype

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