Metabolic Regulation by Leucine of Translation Initiation Through the mTOR-Signaling Pathway by Pancreatic β-Cells
2001
Recent findings have demonstrated that the branched-chain amino acid
leucine can activate the translational regulators, phosphorylated heat- and
acid-stable protein regulated by insulin (PHAS-I) and p70 S6 kinase
(p70 s6k ), in an insulin-independent and rapamycin-sensitive manner
through mammalian target of rapamycin (mTOR), although the mechanism for this
activation is undefined. It has been previously established that
leucine-induced insulin secretion by β-cells involves increased
mitochondrial metabolism by oxidative decarboxylation and allosteric
activation of glutamate dehydrogenase (GDH). We now show that these same
intramitochondrial events that generate signals for leucine-induced insulin
exocytosis are required to activate the mTOR mitogenic signaling pathway by
β-cells. Thus, a minimal model consisting of leucine and glutamine as
substrates for oxidative decarboxylation and an activator of GDH,
respectively, confirmed the requirement for these two metabolic components and
mimicked closely the synergistic interactions achieved by a complete
complement of amino acids to activate p70 s6k in a
rapamycin-sensitive manner. Studies using various leucine analogs also
confirmed the close association of mitochondrial metabolism and the ability of
leucine analogs to activate p70 s6k . Furthermore, selective
inhibitors of mitochondrial function blocked this activation in a reversible
manner, which was not associated with a global reduction in ATP levels. These
findings indicate that leucine at physiological concentrations stimulates
p70 s6k phosphorylation via the mTOR pathway, in part, by serving
both as a mitochondrial fuel and an allosteric activator of GDH.
Leucine-mediated activation of protein translation through mTOR may contribute
to enhanced β-cell function by stimulating growth-related protein
synthesis and proliferation associated with the maintenance of β-cell
mass.
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