Effects of depletion of mitochondrial DNA in metabolism secretion coupling in INS-1 cells.

Kennedy, Eleanor D.; Maechler, Pierre; Wollheim, Claes B.

doi:10.2337/diabetes.47.3.374

Cited by 139 publications

(103 citation statements)

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“…That Vhlh −/− ␤ cells have undergone such a shift in glucose metabolism is supported by the presence of enhanced lactate secretion from Vhlh −/− islets as well as the constitutive production of ATP at low glucose. That mitochondrial activity is critical for normal insulin secretion is further supported by previous work demonstrating that depletion of mitochondrial DNA inhibits glucose-stimulated insulin secretion and that manipulating the activities of LDHA or PDH in ␤-cell lines or isolated rat islets likewise affects pyruvate metabolism with consequent effects on insulin secretion (Kennedy et al 1998;Tsuruzoe et al 1998;Ishihara et al 1999;Ainscow et al 2000;Nicholls et al 2002).…”

Section: Pvhl-hif Regulates Insulin Secretion Genes and Development 3141supporting

confidence: 53%

pVHL is a regulator of glucose metabolism and insulin secretion in pancreatic β cells

Zehetner¹,

Danzer²,

Collins³

et al. 2008

Genes Dev.

107

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Insulin secretion from pancreatic ␤ cells is stimulated by glucose metabolism. However, the relative importance of metabolizing glucose via mitochondrial oxidative phosphorylation versus glycolysis for insulin secretion remains unclear. von Hippel-Lindau (VHL) tumor suppressor protein, pVHL, negatively regulates hypoxia-inducible factor HIF1␣, a transcription factor implicated in promoting a glycolytic form of metabolism. Here we report a central role for the pVHL-HIF1␣ pathway in the control of ␤-cell glucose utilization, insulin secretion, and glucose homeostasis. Conditional inactivation of Vhlh in ␤ cells promoted a diversion of glucose away from mitochondria into lactate production, causing cells to produce high levels of glycolytically derived ATP and to secrete elevated levels of insulin at low glucose concentrations. Vhlh-deficient mice exhibited diminished glucose-stimulated changes in cytoplasmic Ca 2+ concentration, electrical activity, and insulin secretion, which culminate in impaired systemic glucose tolerance. Importantly, combined deletion of Vhlh and Hif1␣ rescued these phenotypes, implying that they are the result of HIF1␣ activation. Together, these results identify pVHL and HIF1␣ as key regulators of insulin secretion from pancreatic ␤ cells. They further suggest that changes in the metabolic strategy of glucose metabolism in ␤ cells have profound effects on whole-body glucose homeostasis.[Keywords: HIF; VHL; glucose intolerance; islet; pancreas] Supplemental material is available at http://www.genesdev.org. Received July 14, 2008; revised version accepted September 5, 2008. During adulthood, cell type-specific growth that exceeds the normal physiological constraints is a common feature of adaptive processes of tissues to changes in metabolic homeostasis and underlies the development of many human diseases, including cancer, heart disease, and diabetes (De Boer et al. 2003;Bouwens and Rooman 2005). Adaptive cell mass expansion, whether neoplastic or nonneoplastic, creates a requirement for compensatory neovascularization to supply oxygen, metabolic substances, and growth/survival factors to the growing tissue (Marti 2005). Therefore, adaptive cell growth responses are generally accompanied, at least initially, by relative states of hypoxia as a result of a mismatch between oxygen demand caused by tissue expansion and oxygen supply provided by the vasculature. An immediate consequence of decreased tissue oxygen availability is that cells shift cellular fuel metabolism from mitochondrial respiration to glycolysis and activate an angiogenic program to increase oxygen delivery in order to overcome the imbalance between tissue mass and vascularization (Semenza 2001;Brahimi-Horn et al. 2007). In this way, tissue function is supported and further mass expansion can occur.At the molecular level, the central regulators of the cellular response to low-oxygen availability are the hypoxia-inducible transcription factors (HIF). HIF are heterodimeric transcription factors composed of HIF1␣, HIF2␣, or HI...

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Section: Pvhl-hif Regulates Insulin Secretion Genes and Development 3141supporting

confidence: 53%

pVHL is a regulator of glucose metabolism and insulin secretion in pancreatic β cells

Zehetner¹,

Danzer²,

Collins³

et al. 2008

Genes Dev.

107

View full text Add to dashboard Cite

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“…These r 0 cells were indeed deficient in oxidative phosphorylation as shown by the absence of detectable cytochrome c oxidase activity. Furthermore, glucose failed to hyperpolarise Dy m and did not increase ATP concentrations in INS-1 r 0 cells [26]. Thus glycolysis alone is not sufficient to generate appropriate increases in ATP.…”

Section: Beta-cell Model Of Mitochondrial Diabetesmentioning

confidence: 99%

“…13). Thus the chemical elimination of mitochondrial DNA leads to complete inhibition of glucose-stimulated insulin secretion [26]. Some experiments have, however, shown that formation of cybrids between enucleated donor cells containing normal mitochondria and r 0 cells of the mouse beta-cell line MIN6 permitted restoration of glucose-induced insulin secretion [70].…”

Section: Beta-cell Model Of Mitochondrial Diabetesmentioning

confidence: 99%

“…Firstly, ATP is generated and transferred to the cytoplasm [25]. Secondly, the membrane potential across the inner mitochondrial membrane (Dy m ) is hyperpolarised, becoming more negative inside [26,30,32]. The cytosolic ATP, or rather the ATP:ADP ratio increases [18,33], causing closure of ATP-sensitive K + (K ATP ) channels.…”

Section: Consensus Model For the Mechanism Of Insulin Secretionmentioning

confidence: 99%

“…Pyruvate, which enters the mitochondria, provides substrate to the Krebs or tricarboxylic acid (TCA) cycle. This generates ATP and other mitochondrial factors, which promote insulin secretion [17,18,22,25,26]. Substrate shuttles across the inner mitochondrial membrane also participate in the generation of mitochondrial signals by glucose [17,27].…”

Section: Consensus Model For the Mechanism Of Insulin Secretionmentioning

confidence: 99%

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

Wollheim¹

2000

Diabetologia

175

148

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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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Evidence for mitochondrial control of neuronal polarity

Mattson

Partin

1999

J. Neurosci. Res.

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An early and essential step in the formation of functional neuronal circuits is the establishment of cell polarity, a process involving the morphological and functional differentiation of the axon (axonogenesis). We now report that treatment of cultured embryonic hippocampal neurons with ethidium bromide (EtBr; an agent that depletes mitochondrial DNA), prior to the establishment of cell polarity, prevents axon formation while permitting outgrowth of minor processes. The polarity-suppressing action of EtBr occurs under conditions of maintained cellular ATP levels, and is not mimicked by ATP-depleting agents (iodoacetate, p-(trifluoromethyoxy)phenylhydrazone [FCCP], and cyanide). Levels of tau, a microtubule-associated protein involved in axonogenesis, were not decreased in neurons treated with EtBr. Electron and confocal microscope analyses showed that EtBr treatment altered mitochondrial ultrastructure and subcellular localization. Basal levels of intracellular calcium were elevated 2- to 3-fold, intramitochondrial calcium levels were greatly increased, and mitochondrial transmembrane potential was decreased in EtBr-treated neurons. Exposure of neurons to a calcium ionophore prevented axonogenesis. Confocal images of intracellular calcium levels and mitochondrial localization in the same cells revealed congregations of mitochondria at the base of the axon associated with local reductions of intracellular calcium levels. When taken together with previous data indicating important roles for calcium in regulating neurite outgrowth, the present findings suggest critical roles for mitochondrial function and modulation of calcium homeostasis in the establishment of neuronal polarity.

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Effects of depletion of mitochondrial DNA in metabolism secretion coupling in INS-1 cells.

Cited by 139 publications

References 0 publications

pVHL is a regulator of glucose metabolism and insulin secretion in pancreatic β cells

pVHL is a regulator of glucose metabolism and insulin secretion in pancreatic β cells

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

Evidence for mitochondrial control of neuronal polarity

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