The transport and accumulation of adenine nucleotides during mitochondrial biogenesis

Abstract

The atractyloside-insensitive accumulation of adenine nucleotides by rat liver mitochondria (as opposed to the exchange-diffusion catalysed by the adenine nucleotide translocase) has been measured by using the luciferin/luciferase assay as well as by measuring [14C]ATP uptake. In foetal rat liver mitochondria ATP is accumulated more rapidly than ADP, whereas AMP is not taken up. The uptake of ATP occurs against a concentration gradient, and the rate of ATP uptake is greater in foetal than in adult rat liver mitochondria. The accumulated [14C]ATP is shown to be present within the mitochondrial matrix space and is freely available to the adenine nucleotide translocase for exchange with ATP present in the external medium. The uptake is specific for ATP and ADP and is not inhibited by adenosine 5'-[beta gamma-imido] triphosphate, GTP, CTP, cyclic AMP or Pi, whereas dATP and AMP do inhibit ATP accumulation. The ATP accumulation is also inhibited by carbonyl cyanide m-chlorophenylhydrazone, KCN and mersalyl but is insensitive to atractyloside. The ATP uptake is concentration-dependent and exhibits Michaelis-Menten kinetics. The divalent cations Mg2+ and Ca2+ greatly enhance ATP accumulation, and the presence of hexokinase inhibits the uptake of ATP by foetal rat liver mitochondria. These latter effects provide an explanation for the low adenine nucleotide content of foetal rat liver mitochondria and the rapid increase that occurs in the mitochondrial adenine nucleotide concentration in vivo immediately after birth.

Inactivation of the Mitochondrial Carrier SLC25A25 (ATP-Mg2+/Pi Transporter) Reduces Physical Endurance and Metabolic Efficiency in Mice

“…Importantly, the ATP transport activity can be activated by cytosolic Ca 2ϩ (28,29) and because variations in the concentration of adenine nucleotides were shown to affect state 3 respiration and ATP synthase-F 0 F 1 activity (26), it is plausible that this carrier plays an important function in the regulation of ATP homeostasis during skeletal muscle contraction. Although, a structural analysis of the purified ATP-Mg 2ϩ/ P i carrier from the mitochondrial membrane has not been achieved (30), structural and functional evidence suggested that SLC25A25 has properties consistent with that of the ATP-Mg 2ϩ/ P i carrier (31,32). SLC25A25 is a member of a family of inner membrane mitochondrial carriers (MC) that function to shuttle metabolites, nucleotides, and cofactors between the cytosol and mitochondria.…”

The calcium-dependent ATP-Mg/Pi mitochondrial carrier is a target of glucose-induced calcium signalling in Saccharomyces cerevisiae

“…The ATP-Mg/P i carrier was first identified in the early 1980s as a transport system responsible for the uptake and accumulation of adenine nucleotides by rat liver mitochondria within the first 2 h after birth [34]. The rapid increase in glycolysis immediately after birth results in a large rise in ATP that would trigger adenine nucleotide accumulation in mitochondria in response to adrenaline and glucagon [35], a process required for post-natal mitochondrial maturation [18].…”

Molecular Basis of MgATP Selectivity of the Mitochondrial SCaMC Carrier

“…Another carrier that transports ATP is the S hort Ca 2+ -binding M itochondrial C arrier (SCaMC) (Chen, 2004; del Arco and Satrustegui, 2004; Fiermonte et al, 2004). While AAC accounts for the bulk ADP/ATP recycling in the matrix, the transport activity of SCaMC is important for mitochondrial activities in the matrix that depend on adenine nucleotides, such as gluconeogenesis and mitochondrial biogenesis (Aprille, 1988; Pollak and Sutton, 1980; Satru´ Stegui et al, 2007; Schild et al, 1999; Traba et al, 2012). …”

“…First, the transport activity of SCaMC is Ca 2+ dependent, i.e., SCaMC remains inactive unless stimulated by a cytosolic Ca 2+ signal (Nosek et al, 1990; Pollak and Sutton, 1980). SCaMC adopts, in addition to the transmembrane domain (TMD) that is homologous to the AAC, an extramembrane N-terminal domain (NTD) that contains four EF-hand motifs in a calmodulin-like arrangement (Fiermonte et al, 2004; Satru´ Stegui et al, 2007; Yang et al, 2014).…”

“…Unlike the AAC that selectively transport free ADP or ATP (Nury et al, 2006), the TMD of SCaMC (SCaMC TMD ) transports MgATP in exchange for phosphate (Pi). It has been shown that the SCaMC TMD has much higher selectivity for MgATP than free ATP, although it can also transport ATP (Austin and Aprille, 1984; Fiermonte et al, 2004; Pollak and Sutton, 1980). Earlier in vivo studies in rat liver mitochondria show that the ATP uptake can be enhanced in the presence of Mg 2+ and is significantly depressed in the absence of Mg 2+ (Austin and Aprille, 1984; Pollak and Sutton, 1980).…”