Calcium Co-regulates Oxidative Metabolism and ATP Synthase-dependent Respiration in Pancreatic Beta Cells

Abstract

Background: Nutrients stimulate calcium dependent activation of energy metabolism, in pancreatic beta cells.Results: Glucose-induced ATP synthase-dependent respiration is strictly calcium-dependent, with little or no effect of calcium on the NAD(P)H response.Conclusion: Calcium coordinates oxidative metabolism and respiration in pancreatic beta cells.Significance: Calcium has novel mitochondrial targets downstream of mitochondrial dehydrogenases.

Calcium release channel RyR2 regulates insulin release and glucose homeostasis

“…The molecular mechanisms underlying insulin secretion and glucose metabolism have not been fully elucidated (1)(2)(3)(4)(5)(6). Numerous studies have demonstrated that calcium (Ca 2+ ) plays a pivotal role in insulin secretion from the islets of Langerhans and that altered cellular Ca 2+ homeostasis may be involved in defective insulin release (7)(8)(9)(10)(11).…”

The Pancreatic β-Cell: A Bioenergetic Perspective

“…Increasing glucose enhances whole cell NAD(P)H autofluorescence (FIGURE 4B) (112,147). Much of the signal is localized to the mitochondria in INS-1 832/13 cells (190), due in part to fluorescence enhancement caused by binding to proteins, including complex I.…”

“…ATP is transported into the vesicles by a nucleotide transporter (170), is co-released with insulin (170), and may provide an autocrine signal acting via P2 receptors to modulate insulin release (65). Most references cite an early study by Detimary et al (123) (112). C: cytosolic ATP in a single dissociated mouse islet cell monitored with GO-ATeam1 during a transition from 2.8 to 25 mM glucose and following oligomycin (506).…”

“…The level of ADP in the same extract has been estimated by difference following conversion of ADP to ATP with phosphoenolpyruvate and pyruvate kinase (171,336). However, this is prone to error at high ATP/ADP ratios, and precision can be improved by hydrolyzing ATP using sulfurylase prior to converting ADP to ATP; this tends to give higher maximal ATP/ADP ratios (112,157,388). HPLC detection of adenine nucleotides in cell extracts has occasionally been employed, with the advantage that AMP can additionally be determined, as can nicotinamide nucleotides for monitoring of redox state (334,405).…”

NCLX Protein, but Not LETM1, Mediates Mitochondrial Ca2+ Extrusion, Thereby Limiting Ca2+-induced NAD(P)H Production and Modulating Matrix Redox State

“…Despite this low affinity, mitochondria can accumulate large amounts of Ca 2ϩ during cell stimulation when exposed to microdomains of high Ca 2ϩ concentration (21), forming in the vicinity of intracellular Ca 2ϩ release or plasma membrane Ca 2ϩ entry channels (22,23). Mitochondrial Ca 2ϩ uptake activates several Ca 2ϩ -dependent matrix enzymes that stimulate energy metabolism (24,25) and ATP synthase-dependent respiration (26). Prolonged (pathological) accumulation of Ca 2ϩ in the matrix space can lead to mitochondrial Ca 2ϩ overload, followed by mitochondrial permeability transition pore opening (27)(28)(29), resulting in the activation of cell death signals (30,31).…”