Role of mitochondrial calcium in metabolism-secretion coupling in nutrient-stimulated insulin release.
Glucose-stimulated insulin release from pancreatic beta cells involves a complex series of signalling pathways. In many forms of diabetes, lesions in this process cause or aggravate the diabetic phenotype. A common motif in these cascades is the elevation of intracellular Ca2+ both in the cytosolic compartment ([Ca2+]c) and within the mitochondria ([Ca2+]m). These parameters can be effectively monitored using the photoprotein aequorin which can be targeted to subcellular compartments by transfection. It is shown that physiological concentrations of glucose elicit [Ca2+]c oscillations measured with fura-2, which correlate well with oscillatory NAD(P)H fluorescence in the mitochondria. Aequorin measurements of [Ca2+]m, though unable to detect oscillations on a single cell basis, reveal large increases in intraorganellar [Ca2+] in response to glucose, elevated amino acid levels and depolarizing concentrations of KCI. These oscillations, in turn, mirror changes in the insulin secretion profile. Since several of the key mitochondrial dehydrogenases involved in oxidative phosphorylation are exquisitely sensitive to changes in [Ca2+], it is proposed that alterations in [Ca2+]m lead to increased activity of the tricarboxylic acid cycle and subsequent ATP production, thereby facilitating exocytosis of insulin from secretory granules. The involvement of the mitochondria in these processes is examined, as is the putative role of efficient mitochondrial genome transcription and translation in normal and diabetic states.
Kennedy
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ED
Département de Médecine Interne, Centre Medical Universitaire, Geneva, Switzerland.
Wollheim
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CB
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D005089:Exocytosis / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D008928:Mitochondria / Q000378:metabolism*; D009991:Oscillometry; D010084:Oxidation-Reduction; D013268:Stimulation, Chemical
D007328:Insulin; D005947:Glucose; D002118:Calcium