Guanine nucleotide transport by atractyloside-sensitive and -insensitive carriers in isolated heart mitochondria

McKee, Edward E.; Bentley, Alice T.; Smith, Raymond L.; Kraas, Jonathan R.; Ciaccio, Christina E.

doi:10.1152/ajpcell.2000.279.6.c1870

Cited by 18 publications

(20 citation statements)

References 15 publications

(36 reference statements)

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“…However, in mammalian cells, other members of the carrier family could carry out the transport of GTP or GDP. For example, isolated rat heart mitochondria have been reported to transport guanine nucleotides, and two distinct transport mechanisms have been identified [7,27,28]. The targeting of a human NDPK (Nm23-H4) to the mitochondrial matrix of ggc1 rescues the iron phenotypic defects of the yeast mutant.…”

Section: Resultsmentioning

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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Section: Resultsmentioning

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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“…The intracellular location of the different isoforms of this enzyme in muscle is not clear, although studies suggest that hepatic nucleoside diphosphokinase is present outside the mitochondrial matrix. There is also evidence that GTP may be transported directly from the mitochondrial matrix on an atractyloside-insensitive carrier, but the rate of transport via this carrier is slower than the well characterized ATP/ADP translocase (23). However, the requirement for guanine nucleotides in non-dividing tissues is low, so that the transport process may be sufficient to meet the physiological requirements for guanine nucleotides in tissues such as skeletal muscle.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of the Cytosolic Form of Phosphoenolpyruvate Carboxykinase (GTP) in Skeletal Muscle Repatterns Energy Metabolism in the Mouse

Hakimi

Yang

Casadesús

et al. 2007

Journal of Biological Chemistry

172

174

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.32) was linked to the ␣-skeletal actin gene promoter, express PEPCK-C in skeletal muscle (1-3 units/g). Breeding two founder lines together produced mice with an activity of PEPCK-C of 9 units/g of muscle (PEPCK-C mus mice). These mice were seven times more active in their cages than controls. On a mouse treadmill, PEPCK-C mus mice ran up to 6 km at a speed of 20 m/min, whereas controls stopped at 0.2 km. PEPCK-C mus mice had an enhanced exercise capacity, with a VO 2max of 156 ؎ 8.0 ml/kg/min, a maximal respiratory exchange ratio of 0.91 ؎ 0.03, and a blood lactate concentration of 3.7 ؎ 1.0 mM after running for 32 min at a 25°grade; the values for control animals were 112 ؎ 21 ml/kg/min, 0.99 ؎ 0.08, and 8.1 ؎ 5.0 mM respectively. The PEPCK-C mus mice ate 60% more than controls but had half the body weight and 10% the body fat as determined by magnetic resonance imaging. In addition, the number of mitochondria and the content of triglyceride in the skeletal muscle of PEPCK-C mus mice were greatly increased as compared with controls. PEPCK-C mus mice had an extended life span relative to control animals; mice up to an age of 2.5 years ran twice as fast as 6 -12-month-old control animals. We conclude that overexpression of PEPCK-C repatterns energy metabolism and leads to greater longevity. PEPCK-C2 is involved in gluconeogenesis in the liver and kidney cortex and in glyceroneogenesis in liver and white and brown adipose tissue (see Ref. 1 for a review). However, this enzyme is also present in a broad variety of mammalian tissues (2), including the small intestine, colon, mammary gland, adrenal gland, lung, and muscle; its metabolic role in these tissues remains obscure. To study the physiological function of PEPCK-C, the gene has been overexpressed or ablated in specific tissues of the mouse. When PEPCK-C was overexpressed in white adipose tissue, the mice had increased rates of glyceroneogenesis in their adipose tissue and became obese (3). In contrast, ablating the expression of PEPCK-C in adipose tissue resulted in mice with lipodystrophy (4). However, a systematic study involving other mammalian tissues where the enzyme has been detected has not been undertaken.We have overexpressed the gene for PEPCK-C in the skeletal muscle of transgenic mice to test the metabolic and physiological consequences. Skeletal muscle was selected as a target organ because there is no clear indication of the metabolic outcome of having a high activity of PEPCK-C in this tissue. Skeletal muscle does not synthesize and release glucose, although there have been reports over the years that the tissue can make glycogen de novo since both PEPCK-C and fructose-1-6-bisphosphatase activities have been found in skeletal muscle (5, 6). We have evidence from research ongoing in our laboratory 3 that glyceroneogenesis occurs in skeletal muscle. This pathway is an abbreviated version of gluconeogenesis, which involves the synthesis of glycerol-3-phosphate (used for triglyceride synthesis) from precursors other than glucose and glycerol. Howe...

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“…GTP salvage inside the matrix is critical because it is believed not to be transported through the inner mitochondrial membrane in higher organisms (Pfaff et al 1965). However, guanine nucleotide transport by atractyloside-sensitive and -insensitive mechanisms in isolated heart mitochondria has been reported by one group (McKee et al 1999(McKee et al , 2000, but the carrier has not been found. On the other hand, it is well established that yeasts harbor a mitochondrial GTP/GDP translocase, but a homologue in higher organisms has not been identified (Vozza et al 2004); accordingly, yeasts lack a GTPforming SUCL (Przybyla-Zawislak et al 1998).…”

Section: Introductionmentioning

confidence: 95%

Exclusive neuronal expression of SUCLA2 in the human brain

et al. 2013

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SUCLA2 encodes the ATP-forming b subunit (A-SUCL-b) of succinyl-CoA ligase, an enzyme of the citric acid cycle. Mutations in SUCLA2 lead to a mitochondrial disorder manifesting as encephalomyopathy with dystonia, deafness and lesions in the basal ganglia. Despite the distinct brain pathology associated with SUCLA2 mutations, the precise localization of SUCLA2 protein has never been investigated. Here, we show that immunoreactivity of A-SUCL-b in surgical human cortical tissue samples was present exclusively in neurons, identified by their morphology and visualized by double labeling with a fluorescent Nissl dye. A-SUCL-b immunoreactivity colocalized [99 % with that of the d subunit of the mitochondrial F 0 -F 1 ATP synthase. Specificity of the anti-A-SUCL-b antiserum was verified by the absence of labeling in fibroblasts from a patient with a complete deletion of SUCLA2. A-SUCL-b immunoreactivity was absent in glial cells, identified by antibodies directed against the glial markers GFAP and S100. Furthermore, in situ hybridization histochemistry demonstrated that SUCLA2 mRNA was present in Nissl-labeled neurons but not glial cells labeled with S100. Immunoreactivity of the GTP-forming b subunit (G-SUCL-b) encoded by SUCLG2, or in situ hybridization histochemistry for SUCLG2 mRNA could not be demonstrated in either neurons or astrocytes. Western blotting of post mortem brain samples revealed minor G-SUCL-b immunoreactivity that was, however, not upregulated in samples obtained from diabetic versus nondiabetic patients, as has been described for murine brain. Our work establishes that SUCLA2 is expressed exclusively in neurons in the human cerebral cortex.

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Guanine nucleotide transport by atractyloside-sensitive and -insensitive carriers in isolated heart mitochondria

Cited by 18 publications

References 15 publications

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

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

Overexpression of the Cytosolic Form of Phosphoenolpyruvate Carboxykinase (GTP) in Skeletal Muscle Repatterns Energy Metabolism in the Mouse

Exclusive neuronal expression of SUCLA2 in the human brain

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