ATP synthesis and storage

Abstract

Since 1929, when it was discovered that ATP is a substrate for muscle contraction, the knowledge about this purine nucleotide has been greatly expanded. Many aspects of cell metabolism revolve around ATP production and consumption. It is important to understand the concepts of glucose and oxygen consumption in aerobic and anaerobic life and to link bioenergetics with the vast amount of reactions occurring within cells. ATP is universally seen as the energy exchange factor that connects anabolism and catabolism but also fuels processes such as motile contraction, phosphorylations, and active transport. It is also a signalling molecule in the purinergic signalling mechanisms. In this review, we will discuss all the main mechanisms of ATP production linked to ADP phosphorylation as well the regulation of these mechanisms during stress conditions and in connection with calcium signalling events. Recent advances regarding ATP storage and its special significance for purinergic signalling will also be reviewed.

Fig. 1

ATP management within the cell. Schematic representation of mechanisms of ATP synthesis and storage inside the cell. Glycolysis is represented in the yellow and blue boxes, the TCA cycle by the green circle, and oxidative phosphorylation in the orange box. Reduction of pyruvate to lactate is represented inside the red dotted rectangle. Hypothetical contacts between ATP storage vesicles and mitochondria, with preferential ATP transfer, are shown within the red dotted circle

Fig. 2

Protein-kinase cascade involved in fundamental pathways sensitive to the energy charge. The activity of AMPK is related to the phosphorylation of several downstream substrates capable of altering gene and protein expression, in response to a situation of metabolic and energy crisis due to a deep alteration in ATP synthesis and production. AMPK is a heterotrimeric complex composed of catalytic α-subunits and regulatory β- and γ-subunits, where the major regulatory phosphorylation site is Thr¹⁷², phosphorylated by LKB1 (Liver Kinase B1) and CaMKK (calmodulin-dependent protein kinase kinase), respectively. AMPK acts to conserve energy by directing metabolism towards ATP production while inhibiting pathways that utilize ATP. Its major downstream targets are mTOR (mammalian target of rapamycin) and p53, modulating autophagy and cell cycle regulation processes in order to restore the intracellular energy balance

Fig. 3

Mitochondrial Ca²⁺ dynamics and stimulation of the TCA cycle and oxidative phosphorylation during mitochondrial ATP production. The direct transfer of Ca²⁺ from the ER to mitochondria supports oxidative phosphorylation during mitochondrial ATP production. This is an example of metabolic crosstalk between these organelles and characterizes the importance of ER/SR–mitochondria contacts. Schematic mitochondrial Ca²⁺ uptake and efflux mechanisms are displayed in grey. All enzymes and protein complexes stimulated or influenced by Ca²⁺ during mitochondrial ATP production are displayed in red. (MCU, mitochondrial calcium uniporter; mRyR, mitochondrial ryanodine receptor; RAM, rapid mode; VDAC, voltage-dependent anionic channel; PTP, permeability transition pore; ANT, adenine nucleotide transporter; PDH, pyruvate dehydrogenase; ICDH, isocitrate dehydrogenase; KDH, a-ketogluterate dehydrogenase; AGC1/2, aralar and citrin aspartate/glutamate carriers; MAM, mitochondrial–endoplasmic reticulum associated membranes)