Mitochondrial glucose metabolism

Insulin secretion and metabolism

Website References

Mitochondrial glucose metabolism

Both cytosolic pyruvate and NADH enter the mitochondria and are metabolized to produce ATP (Figure 2). The glycolytic factor NADH enters the mitochondria via two NADH shuttle systems, the glycerol-phosphate and the malate-aspartate shuttle systems (MacDonald, 1982;Giroix et al., 1991;Sener & Malaisse, 1992;Eto & Kadowaki, 1999). These shuttles may play an important role in the regulation of insulin secretion (MacDonald, 1990). In support of this idea, glycerol phosphate shuttle and mGPDH activities are very high in β-cells relative to other mammalian cells (MacDonald, 1990). Recently, further support for the model has come from studies in which mitochondria glycerol phosphate dehydrogenase (mGPDH) was knocked out in transgenic mice (mGPDH (-/-) mice) (Eto et al., 1999). While mGPDH (-/-) mouse islets or suppression of malate/aspartate shuttle activity alone in wild type islets had no effect on GSIS, combined blockade of the two shuttles completely ablated glucose responsiveness. The results from this study suggested that these NADH shuttle systems are the major regulatory pathways for GSIS.

In addition to cytosolic NADH, NADH is also produced from pyruvate in the mitochondria by the TCA cycle. Both cytosolic and mitochondrial sources of NADH stimulate the electron transport chain to pump H⁺ ions out of the mitochondrial matrix, across the inner membrane, hyperpolarizing the inner mitochondrial membrane (Eto et al., 1999;Eto & Kadowaki, 1999;Kennedy et al., 1998;Duchen et al., 1993;Maechler et al., 1997). Although these are important steps in GSIS, which source of NADH is more important still remains to be determined. Once cytosolic Ca²⁺ has been elevated (see the next section), the hyperpolarization of the mitochondrial inner membrane can

stimulate the mitochondrial membrane potential-dependent Ca²⁺-uniporter to increase matrix mitochondrial Ca²⁺ concentration (Litsky & Pfeiffer, 1997), leading to a further augmentation of Ca²⁺-dependent dehydrogenase activity and an increase in production of NADH and ATP from the TCA cycle (Hansford, 1991). A rise in matrix Ca²⁺ may also promote dissociation of an ATP synthase inhibitor, providing a positive feedback mechanism on ATP production (Territo et al., 2000;Moreno-Sanchez, 1985). In addition, the increase in mitochondrial Ca²⁺ can further stimulate ATP transport into the cytosol, increasing cytosolic ATP concentration and the ATP/ADP ratio (Moreno-Sanchez, 1985) (Figure 2).