Mitochondrial signals drive insulin secretion in the pancreatic β-cell

• Published in: Molecular and cellular endocrinology 2012-04, Vol.353 (1-2), p.128-137
• Main Authors: Wiederkehr, Andreas, Wollheim, Claes B.
• Format: Article
• Language: English
• Subjects: adenosine triphosphate; Adenosine Triphosphate - biosynthesis; alkalinization; Animals; Calcium; Calcium - metabolism; Cell Membrane - metabolism; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - pathology; Diabetes Mellitus, Type 2 - therapy; Exocytosis; Humans; insulin; Insulin - metabolism; Insulin Secretion; Insulin-Secreting Cells - metabolism; Insulin-Secreting Cells - pathology; Islet; islets of Langerhans; Membrane Potentials; Metabolism–secretion coupling; metabolites; mitochondria; Mitochondria - metabolism; Mitochondrial matrix pH; noninsulin-dependent diabetes mellitus; oxidation; Oxidative Phosphorylation; plasma membrane; S100G; signal transduction; β-Cell
• ISSN: 0303-7207; 1872-8057
• DOI: 10.1016/j.mce.2011.07.016

► Importance of mitochondria in β-cell metabolism-secretion coupling. ► Translation of nutrient stimulation into mitochondrial activation. ► Mitochondria derived signals essential for insulin secretion. ► Mitochondrial calcium a signal for the amplification of insulin secretion. ► Mitochondrial matrix pH controls β-cell energy metabolism. β-Cell nutrient sensing depends on mitochondrial function. Oxidation of nutrient-derived metabolites in the mitochondria leads to plasma membrane depolarization, Ca2+ influx and insulin granule exocytosis. Subsequent mitochondrial Ca2+ uptake further accelerates metabolism and oxidative phosphorylation. Nutrient activation also increases the mitochondrial matrix pH. This alkalinization is required to maintain elevated insulin secretion during prolonged nutrient stimulation. Together the mitochondrial Ca2+ rise and matrix alkalinization assure optimal ATP synthesis necessary for efficient activation of the triggering pathway of insulin secretion. The sustained, amplifying pathway of insulin release also depends on mitochondrial Ca2+ signals, which likely influence the generation of glucose-derived metabolites serving as coupling factors. Therefore, mitochondria are both recipients and generators of signals essential for metabolism-secretion coupling. Activation of these signaling pathways would be an attractive target for the improvement of β-cell function and the treatment of type 2 diabetes.