Regulation of ATP production by mitochondrial Ca2+

Abstract

Stimulation of mitochondrial oxidative metabolism by Ca2+ is now generally recognised as important for the control of cellular ATP homeostasis. Here, we review the mechanisms through which Ca2+ regulates mitochondrial ATP synthesis. We focus on cardiac myocytes and pancreatic β-cells, where tight control of this process is likely to play an important role in the response to rapid changes in workload and to nutrient stimulation, respectively. We also describe a novel approach for imaging the Ca2+-dependent regulation of ATP levels dynamically in single cells.

A computational model of lysosome-ER Ca2+ microdomains

“…Ca 2+ signalling between the ER and the plasma membrane or organelles, such as mitochondria, is a well-characterised constituent of the Ca 2+ signalling network (Helle et al, 2013). For example, mitochondria form tight (,10 nm) physical junctions with the ER in many cell types allowing mitochondrial uptake of ER-released Ca 2+ , thereby matching mitochondrial ATP production to cellular demand (Csordás et al, 2006;Szabadkai et al, 2006;Tarasov et al, 2012). Furthermore, in cardiac muscle, a strongly coupled Ca 2+ microdomain in the dyadic cleft junction (,15-nm wide) between L-type Ca 2+ channels on the plasma membrane and clusters of ryanodine receptors on the SR is crucial for excitation-contraction coupling (Bers, 2002;Franzini-Armstrong et al, 1999;Schendel et al, 2012).…”

Mitochondrial Matrix Ca2+ Accumulation Regulates Cytosolic NAD+/NADH Metabolism, Protein Acetylation, and Sirtuin Expression

“…Specifically, mitochondrial Ca 2ϩ uptake regulates bioenergetics both by increasing the supply of reducing equivalents (NADH production) to the electron transport chain and by increasing F 1 -F o ATP synthase activity (NADH consumption) (4,5). The balance between NADH production and NADH oxidation is therefore exquisitely dependent upon both the shape and duration of the mitochondrial Ca 2ϩ signal to activate NADH-generating matrix enzymes, as well as the rate of NADH consumption by the respiratory chain (6).…”

Mitochondrial Metabolism in T Cell Activation and Senescence: A Mini-Review

“…At the immune synapse, mitochondrial Ca +2 uptake prevents Ca +2 -dependent inactivation of the channels, and thereby supports sustained Ca +2 -dependent signaling [16,17,18,19]. In addition, Ca +2 uptake has a direct effect on mitochondrial function [20,21]; Ca +2 directly activates key mitochondrial enzymes, causing an increase in tricarboxylic acid (TCA) cycle flux (reviewed in [22]). …”

“…PDH activity is rate limiting for glucose oxidation by the mitochondria, and therefore directly affects the rate of mitochondrial respiration and ATP production [27]. Isocitrate dehydrogenase is a TCA cycle enzyme that catalyzes the oxidative decarboxylation of isocitrate to produce α-ketoglutarate and CO 2 , while reducing NAD + to NADH [22]. α-Ketoglutarate dehydrogenase, another TCA cycle enzyme, converts α-ketoglutarate and CoA to succinyl-CoA and CO 2 .…”