Maternally transmitted diabetes and deafness associated with a 10.4 kb mitochondrial DNA deletion

Ballinger, Scott W.; Shoffner, John M.; Hedaya, Ellis V.; Trounce, Ian A.; Polak, Meraida; Koontz, Deborah; Wallace, Douglas C.

doi:10.1038/ng0492-11

Cited by 571 publications

(257 citation statements)

References 29 publications

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“…At 0400 hours of each inpatient period, a priming dose of L-[1,2-13 C]leucine (1.8 mg͞kg of FFM) was administered through a peripheral forearm vein. This was followed by a continuous infusion of L- [1,[2][3][4][5][6][7][8][9][10][11][12][13] C]leucine (1.8 mg͞kg of FFM per h). Insulin [1.5 milliunits (mU)͞kg of FFM per min] or normal saline infusion was randomized and began at 0700 hours.…”

Section: Methodsmentioning

confidence: 99%

“…However, the effect of insulin on skeletal muscle mitochondrial function and oxidative capacity have not been defined. Previous studies have suggested a relationship between insulin action and the oxidative capacity of skeletal muscle (3)(4)(5)(6)(7)(8)(9)(10). For example, the ratio between oxidative and glycolytic enzyme activities is decreased in skeletal muscle from type 2 diabetic subjects compared with nondiabetic subjects (6).…”

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confidence: 99%

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Effect of insulin on human skeletal muscle mitochondrial ATP production, protein synthesis, and mRNA transcripts

Stump

Short

Bigelow

et al. 2003

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

419

369

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Mitochondria are the primary site of skeletal muscle fuel metabolism and ATP production. Although insulin is a major regulator of fuel metabolism, its effect on mitochondrial ATP production is not known. Here we report increases in vastus lateralis muscle mitochondrial ATP production capacity (32-42%) in healthy humans (P < 0.01) i.v. infused with insulin (1.5 milliunits͞kg of fat-free mass per min) while clamping glucose, amino acids, glucagon, and growth hormone. Increased ATP production occurred in association with increased mRNA levels from both mitochondrial (NADH dehydrogenase subunit IV) and nuclear [cytochrome c oxidase (COX) subunit IV] genes (164 -180%) encoding mitochondrial proteins (P < 0.05). In addition, muscle mitochondrial protein synthesis, and COX and citrate synthase enzyme activities were increased by insulin (P < 0.05). Further studies demonstrated no effect of low to high insulin levels on muscle mitochondrial ATP production for people with type 2 diabetes mellitus, whereas matched nondiabetic controls increased 16 -26% (P < 0.02) when four different substrate combinations were used. In conclusion, insulin stimulates mitochondrial oxidative phosphorylation in skeletal muscle along with synthesis of gene transcripts and mitochondrial protein in human subjects. Skeletal muscle of type 2 diabetic patients has a reduced capacity to increase ATP production with high insulin levels.cytochrome c oxidase ͉ NADH dehydrogenase subunit IV ͉ amino acids ͉ citrate synthase

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Effect of insulin on human skeletal muscle mitochondrial ATP production, protein synthesis, and mRNA transcripts

Stump

Short

Bigelow

et al. 2003

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

419

369

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“…[24][25][26] An increased frequency of these extensively deleted genomes may be associated with pathological states, although they exist in normal tissue. 27 These deletions may persist as partial duplications, or may be generated at a high frequency.…”

Section: Light-strand Origins Of Replicationmentioning

confidence: 99%

Genesis and Wanderings: Origins and Migrations in Asymmetrically Replicating Mitochondrial DNA

Brown¹,

Clayton²

2006

Cell Cycle

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Mammalian mitochondria maintain a small circular genome that encodes RNA and polypeptides that are essential for the generation of ATP through oxidative phosphorylation. The mechanism of replication of mammalian mitochondrial DNA (mtDNA) has recently been a topic of controversy. New evidence has led to a modified strand-displacement model that reconciles much of the current data. This revision stems from a new appreciation for alternative light-strand origins. We consider here some of the potential mechanisms for light-strand origin initiation. We also consider further the susceptibility of branch migration within replicating mtDNA molecules. The existence of alternative light-strand origins and a propensity for branch migration in replicating mtDNA molecules exposes a new array of possible configurations of mtDNA. The assortment and assignment of these forms is relevant to the interpretation of experimental data and may also yield insight into the molecular basis of replication errors.

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“…In 1992, linkage was described between mitochondrial DNA mutations and diabetes for both a deletion [64] and a point mutation [65]. The mitochondrial genome is a compact doublestranded DNA containing almost exclusively coding regions.…”

Section: Role Of Mitochondrial Dna In Insulin Secretionmentioning

confidence: 99%

Beta-cell mitochondria in the regulation of insulin secretion: a new culprit in Type II diabetes

Wollheim¹

2000

Diabetologia

176

149

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In previous lectures, Claude Bernard's many scientific contributions have been highlighted. Among others he suggested in 1850 that the liver stores glucose and 7 years later, in 1857, he finally isolated glycogen [2]. Before that, in 1849, Claude Bernard reported his ªPiqßre sucrØeº to the SociØtØ de Biologie, Paris [3]. In analogy to his experiments in which stimulation of the fifth cranial nerve caused saliva secretion, he assumed that stimulation of the vagus nerve would elicit glucose secretion from the liver. In unanaesthetised rabbits and dogs, the pricking of the bottom of the fourth ventricle resulted in pronounced hyperglycaemia and glucosuria within 20 min. The ªdiabetesº was transient and disappeared after a few hours. He later showed that this effect was mediated, not by the vagus, but by sympathetic nerves. His discovery of glycogen made Claude Bernard the true father of Diabetologia (2000) AbstractInsulin is stored in secretory granules in the beta-cell and is secreted by exocytosis. This process is precisely controlled to achieve blood glucose homeostasis. Many forms of diabetes mellitus display impaired glucose-induced insulin secretion. This has been shown to be the primary cause of the disease in the various forms of maturity-onset diabetes of the young (MODY) and has also been implicated in adult-onset Type II (non-insulin-dependent) diabetes mellitus. Glucose generates ATP and other metabolic coupling factors in the beta-cell mitochondria. By plasma membrane depolarisation ATP promotes Ca 2+ influx, which raises cytosolic Ca 2+ and triggers insulin exocytosis. Through hyperpolarisation of the mitochondrial membrane glucose also increases the Ca 2+ concentration in the mitochondrial matrix activating Ca 2+ -sensitive dehydrogenases in the tricarboxylic acid cycle. The resulting generation of glutamate participates in Ca 2+ -stimulated exocytosis. Mitochondrial DNA (mtDNA) encodes some of the polypeptides of the respiratory chain enzyme complexes. Mutations in mtDNA lead to maternally inherited diabetes mellitus characterised by impaired insulin secretion. The impact of altered mtDNA on insulin secretion has been shown in mtDNA-deficient beta-cell lines which have lost glucose-stimulated insulin secretion but retain a Ca 2+ -induced insulin secretion. A cellular model of MODY3 expressing dominant-negative hepatocyte nuclear factor-1a (HNF-1a) also displayed deletion of glucose-induced but not Ca 2+ -induced insulin secretion. Reduced mitochondrial metabolism explains this secretory pattern. Thus, genetically manipulated beta-cell lines are essential tools in the investigation of the molecular basis of beta-cell dysfunction in diabetes and should explain the role of other transcription factors in the disease. [Diabetologia (2000) 43: 265±277]

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Maternally transmitted diabetes and deafness associated with a 10.4 kb mitochondrial DNA deletion

Cited by 571 publications

References 29 publications

Effect of insulin on human skeletal muscle mitochondrial ATP production, protein synthesis, and mRNA transcripts

Effect of insulin on human skeletal muscle mitochondrial ATP production, protein synthesis, and mRNA transcripts

Genesis and Wanderings: Origins and Migrations in Asymmetrically Replicating Mitochondrial DNA

Beta-cell mitochondria in the regulation of insulin secretion: a new culprit in Type II diabetes

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