Implicacion de aralar/agc1/sic25a12,el transportador mitocondrial de aspartato-glutamato, y su dependencia funcional de ca2+ en el metabolismo de la glucosa responsable de la secreción de insulina en la celula-b

Tesis doctoral de Patricia Marmol Carrasco

Aralar (agc1) is one of the isoforms of the mitochondrial aspartate-glutamate carrier, and the key component of the malate-aspartate shuttle (mas), which is involved in the transfer of redox equivalents produced in glycolysis from cytosol to mitochondria. aralar has ca 2+ -binding motifs (ef-hands) in its n-terminal portion facing the mitochondrial intermembrane space. Previous studies from our laboratory have shown that mas activity is activated by cytosolic ca 2+ with a s 0.5 of ~300 nm in brain, heart and skeletal muscle; below the km of the ca 2+ uniporter, and thus, mas activation by ca 2+ constitutes a mechanism for transducing ca 2+ signals to mitochoondria independent of the ca 2+ uniporter. the importance of aralar in metabolic glucose signalling in íY-cells has been addressed by silencing of aralar in ins-1 íY-cells which resulted in a completely abolition of mas activity. Under these conditions, glucose-induced insulin secretion (gsis) and mitochondrial nad(p)h formation were inhibited by 20-25%. the importance of ca 2+ -binding by aralar was addressed by introducing mutations in aralar which blocked ca 2+ -binding. As these mutations abolish ca 2+ activation of mas, while preserving its basal activity, mas activation by ca 2+ in mitochondria from ins-1 íY-cells is clearly conferred by its functional ef-hand pair composed of ef1-ef2. Mas was found to have a ca 2+ requirement to be operative in intact ins-1 íY-cells, as glucosestimulated nad(p)h formation in mitochondria seems to correspond to pyruvate oxidation in the total absence of extracellular ca 2+ , without any participation of aralar. When small cytosolic ca 2+ signals are applied, mitochondrial nad(p)h formation induced by glucose is potentiated in intact ins-1 íY-cells, and this potentiation does not take place when aralar has mutations in its ef1-ef2 ca 2+ -binding motifs. the hypothesis that a single aralar allele may be a risk factor for the development of type 2 diabetes in mice after a year long high fat diet was tested. The results showed that even after this long lipotoxic treatment, insulin secretion was maintained. However, old aralar +/- mice had a tendency towards a decreased insulin resistance compared to wild-type mice, possibly involving the muscle.

 

Datos académicos de la tesis doctoral «Implicacion de aralar/agc1/sic25a12,el transportador mitocondrial de aspartato-glutamato, y su dependencia funcional de ca2+ en el metabolismo de la glucosa responsable de la secreción de insulina en la celula-b«

  • Título de la tesis:  Implicacion de aralar/agc1/sic25a12,el transportador mitocondrial de aspartato-glutamato, y su dependencia funcional de ca2+ en el metabolismo de la glucosa responsable de la secreción de insulina en la celula-b
  • Autor:  Patricia Marmol Carrasco
  • Universidad:  Autónoma de Madrid
  • Fecha de lectura de la tesis:  28/10/2009

 

Dirección y tribunal

  • Director de la tesis
    • Beatriz Pardo Merino
  • Tribunal
    • Presidente del tribunal: José manuel Cuezva marcos
    • eduardo Rial zueco (vocal)
    • m gema Medina gomez (vocal)
    • María del mar Gonzalez barroso (vocal)

 

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