Mitochondrial-mediated suppression of ROS production upon exposure of neurons to lethal stress: mitochondrial targeted preconditioning

Abstract

Preconditioning represents the condition where transient exposure of cells to an initiating event leads to protection against subsequent, potentially lethal stimuli. Recent studies have established that mitochondrial-centered mechanisms are important mediators in promoting development of the preconditioning response. However, many details concerning these mechanisms are unclear. The purpose of this review is to describe the initiating and subsequent intracellular events involving mitochondria which can lead to neuronal preconditioning. These mitochondrial specific targets include: 1) potassium channels located on the inner mitochondrial membrane; 2) respiratory chain enzymes; and 3) oxidative phosphorylation. Following activation of mitochondrial ATP-sensitive potassium (mitoK(ATP)) channels and/or increased production of reactive oxygen species (ROS) resulting from the disruption of the respiratory chain or during energy substrate deprivation, morphological changes or signaling events involving protein kinases confer immediate or delayed preconditioning on neurons that will allow them to survive otherwise lethal insults. While the mechanisms involved are not known with certainty, the results of preconditioning are the enhanced neuronal viability, the attenuated influx of intracellular calcium, the reduced availability of ROS, the suppression of apoptosis, and the maintenance of ATP levels during and following stress.

Figure 1

Schematic illustration showing signaling events which occur following opening of mitoK_ATP channels or liberation of ROS from the protein complexes which form the electron transport chain. These two initiating events, which can occur separately or together, lead to the activation of intramitochondrial and intracellular signaling mechanisms. The final result of preconditioning is the protection of neurons during and following exposure to potentially lethal stresses, due to the sustained depolarization of mitochondria, the attenuation of intracellular calcium influx, the elimination of the ROS surge, the preservation of ATP levels, the prevention of apoptosis, and the maintenance of normal mitochondrial morphology. Abbreviations: ΔΨm, mitochondrial membrane potential; O₂⁻, superoxide anion; H₂O₂, hydrogen peroxide; Ca²⁺, calcium; ADP, adenosine di-phosophate; ATP, adenosine tri-phosphate; PKC, protein kinase C; Gsk3β, phospho-glycogen synthase kinase 3 beta; PI3K, phosphoinositide 3-kinase; Bad, Bcl-2 associated death promoter, Akt; protein kinase B.