Redox implications of AMPK-mediated signal transduction beyond energetic clues

Abstract

SummarySince the discovery of AMP-dependent protein kinase (AMPK), its fundamental role in regulating metabolic pathways and the molecular mechanism underlying the regulation of its activity by adenine nucleotides has been widely studied. AMPK is not only an energy-responsive enzyme, but it also senses redox signals. This review aims at recapitulating the recent lines of evidence that demonstrate the responsiveness of this kinase to metabolic and nitroxidative imbalance, thus providing new insights into the intimate networks of redox-based signals upstream of AMPK. In particular, we discuss its well-recognized activation downstream of mitochondrial dysfunction, debate the recent findings that AMPK is directly targeted by pro-oxidant species, and question alternative redox pathways that allow AMPK to be included into the large class of redox-sensing proteins. The possible therapeutic implications of the role of AMPK in redox-associated pathologies, such as cancer and neurodegeneration, are also discussed in light of recent advances that suggest a role for AMPK in the tuning of redox-dependent processes, such as apoptosis and autophagy.Key words: ROS, Apoptosis, Autophagy, Nitric oxide Introduction Living organisms derive energy from the breakdown of the molecular bonds of nutrients, and then convert it into the more usable forms of ATP and NADPH (see Box 1). Cell homeostasis depends on the maintenance of ATP levels, whose hydrolysis can be coupled to synthesis reactions, transport across membranes and other endoergonic processes. For this reason, cells actively synthesize ATP and have evolved molecular mechanisms aimed at counteracting even slight decreases of ATP (Hardie, 2011). The mutual regulation of the ATP-regenerating and ATP-consuming processes, however, does not depend on the concentration of this single metabolite, but is in response to the energy balance of the cell (Atkinson, 1970). Indeed, the concentration of ATP, which has been estimated to range from 1 to 10 mM, can be subjected to marked variations. Therefore, the absolute intracellular ATP concentration tightly depends on the concentration of the other adenylates (adenylate pool) and should be considered as a function of the adenylate energy charge, which, in accordance

5′-AMP-Activated Protein Kinase Attenuates Adriamycin-Induced Oxidative Podocyte Injury through Thioredoxin-Mediated Suppression of the Apoptosis Signal-Regulating Kinase 1–P38 Signaling Pathway

“…Indeed, activation of ASK1 by ADR was transient and was followed by suppressed ASK1 activities, as compared with control. ROS-induced activation of AMPK, as reported by many investigators (Irrcher et al, 2009;Mungai et al, 2011;Cardaci et al, 2012), should also be able to promote Trx-ASK1 interaction. We have also tried to confirm the role of AMPK by using genetic approaches.…”

“…First, both Trx and ASK1 have been reported to be critically involved in pathologic situations such as inflammation, tumor, neurodegeneration, aging, and cell injury (Matsuzawa and Ichijo, 2008;Al-Gayyar et al, 2011). The importance of AMPK in these pathologic situations has also been well documented (Hallows et al, 2010;Cardaci et al, 2012). It is possible that the action of AMPK might be through modification of ASK1-Trx interaction.…”

“…It is also worth mentioning that the interaction between Trx and ASK1 was, in fact, stimulated by ADR. This phenomenon may be explained by the increased self-defense mechanisms against ROS, including activation of AMPK (Irrcher et al, 2009;Mungai et al, 2011;Cardaci et al, 2012). Indeed, activation of ASK1 by ADR was transient and was followed by suppressed ASK1 activities, as compared with control.…”

Glucose and palmitate uncouple AMPK from autophagy in human aortic endothelial cells

“…We hypothesized that autophagy impairment observed in the presence of high concentrations of glucose and palmitate could be due to decreased AMPK activity. We assessed AMPK activity in HAECs by measuring in vitro the phosphorylation of SAMS peptide (30) and in vivo the phosphorylation of AMPK on Thr172, a modification that is both required for AMPK activation and often used as a surrogate marker for its activity (12). Compared with control-treated cells, HAECs exposed to high concentrations of glucose and palmitate had reduced AMPK activity as demonstrated by both the SAMS peptide (Fig.…”

Evidence that a mitochondrial death spiral underlies antagonistic pleiotropy

“…This Foxo activation is necessary for activated JNK to increase lifespan (Wang et al ., 2005). Although the mechanism underlying the Tor inhibition that occurs under high ROS is not completely clear, it is possible that a role is played by the ROS‐dependent activation of AMPK (Cardaci et al ., 2012), which inhibits Tor both by phosphorylating and activating the Tor inhibitor Tsc1/Tsc2 (Fig. 1; Inoki et al ., 2003) and by phosphorylating and inhibiting the Tor‐associated scaffold Raptor (Gwinn et al ., 2008).…”