Mitochondrial targets for volatile anesthetics against cardiac ischemia-reperfusion injury

Abstract

Mitochondria are critical modulators of cell function and are increasingly recognized as proximal sensors and effectors that ultimately determine the balance between cell survival and cell death. Volatile anesthetics (VA) are long known for their cardioprotective effects, as demonstrated by improved mitochondrial and cellular functions, and by reduced necrotic and apoptotic cell death during cardiac ischemia and reperfusion (IR) injury. The molecular mechanisms by which VA impart cardioprotection are still poorly understood. Because of the emerging role of mitochondria as therapeutic targets in diseases, including ischemic heart disease, it is important to know if VA-induced cytoprotective mechanisms are mediated at the mitochondrial level. In recent years, considerable evidence points to direct effects of VA on mitochondrial channel/transporter protein functions and electron transport chain (ETC) complexes as potential targets in mediating cardioprotection. This review furnishes an integrated overview of targets that VA impart on mitochondrial channels/transporters and ETC proteins that could provide a basis for cation regulation and homeostasis, mitochondrial bioenergetics, and reactive oxygen species (ROS) emission in redox signaling for cardiac cell protection during IR injury.

Keywords: cardiac IR injury; cardioprotection; electron transport chain; isoflurane; mitochondrial bioenergetics; volatile anesthetics.

Figure 1

Targets of mitochondria and sequence of changes in cytosolic and mitochondrial function during cardiac ischemia and reperfusion (IR) injury. During ischemia (A) reduced O₂ promotes anaerobic glycolysis that generates increased cytosolic lactate (lac_c) leading to acidification. Increased H⁺ activates Na⁺-H⁺ exchanger (NHE) leading to increase cytosolic Na⁺ ([Na⁺]_c), which activates Na⁺-Ca²⁺ exchanger (NCE), causing an increase in cytosolic Ca²⁺ ([Ca²⁺]_c) which in turn increases mitochondrial matrix Ca²⁺ ([Ca²⁺]_m). Impaired electron transport leads to increased generation of reactive oxygen species (ROS) beginning with superoxide (O^·−₂); impaired respiration and substrate utilization leads to uncoupling with lowered mitochondrial membrane potential (ΔΨ_m) and decreased generation of mitochondrial ATP. During reperfusion (B), the increase in deleterious ROS damages major macromolecules including tricarboxlic acid (TCA) enzymes, membrane transporters, electron transport chain (ETC) proteins and mitochondrial DNA (mtDNA). Also during reperfusion, ΔΨ_m is restored and [Ca²⁺]_m and ROS further increase to produce even greater mitochondria damage that induces mitochondrial permeability transition pore (mPTP) opening and release of cytochrome c (cyt C) that in turn triggers apoptosis. Other abbreviations: OMM, outer mitochondrial membrane; IMM, inter mitochondrial membrane; IMS, inter mitochondrial space.

Figure 2

A proposed view of cardioprotection by effects of volatile anesthetics (VA) on electron transport chain (ETC) proteins and on ADP/ATP transport via voltage-dependent anion channel (VDAC). By direct attenuation of NADH dehydrogenase (complex I) and cytochrome bc₁ (complex III), VA promote a slightly more reduced redox state and a slowing of the rates of respiration and phosphorylation. Lowered ATP entry into the matrix through VDAC/ANT may contribute to reduced ATPase activity. These events may help to decrease ATP hydrolysis and so to better maintain cell ATP levels during reperfusion. Preserved ATP synthesis at complex V would diminish the need for glycolysis while decreasing lactic acidosis and cytosolic Ca²⁺ [Ca²⁺]_c (see details in Figure 1 legend). Other abbreviations: ROS, reactive oxygen species; mPTP, mitochondrial permeability transition pore; Symbol represents reverse functioning of NHE and NCE.

Figure 3

A proposed view of cardioprotection by effects of volatile anesthetics (VA) on mitochondrial Ca²⁺ overload. VA could mediate cardioprotection by mildly inhibiting mitochondrial NCE to increase [Ca²⁺]_m which triggers protective mechanisms before IR injury. Lowered ATP or higher Ca²⁺ -induced stimulation of mitochondrial K⁺ channels may lead to mild uncoupling by the K⁺-H⁺ exchanger (KHE) that may reduce ΔΨ_m and [Ca²⁺]_m during IR via the mitochondrial Ca²⁺ uniporter (CU) and/or the putative mitochondrial ryanodine receptor (mRyR). Lowered [Ca²⁺]_m would decrease “deleterious” ROS emission, impede mPTP opening, and reduce apoptotic/necrotic cell death on reperfusion. mPTP opening could also be prevented by a VA-mediated decrease in activation of glycogen synthase kinase (GSK-3β) via phosphorylation of GSK-3β. Effects of VA on channels/exchangers suggest potential implications for low Ca²⁺ and ROS in the triggering phase of VA cardioprotection.

Figure 4

A proposed view of cardioprotection based on the modulating effects of volatile anesthetics (VA) on electron transport chain (ETC) function in the presence of different substrates. Mitochondria generate reducing equivalents, NADH₂ and FADH₂, via the tricarboxylic acid (TCA) cycle in the matrix during electron transfer through the ETC complexes of the inner mitochondrial membrane (IMM) to generate the proton gradient (H⁺) and mitochondrial membrane potential (ΔΨ_m). The transfer of electrons through the ETC complexes to the final electron acceptor, O₂, is coupled with the H⁺ gradient to phosphorylate ADP to ATP by ATP synthase (complex V). During electron transfer, attenuation of complex I and complex III generates O₂ free radical anions (O^·−₂) leading to other ROS. Complex II mediates forward and reverse electron transfer (FET and RET, respectively), which generates ROS at complex I and complex III. VA modulate complex I and III, therefore affecting bioenergetics (ΔΨ_m, redox state, respiration, phosphorylation). During oxidation of complex II substrate succinate (Suc), ROS generated via RET may be considered “deleterious,” while ROS generated via FET by complex III inhibition may represent the “signaling” ROS. VA-induced complex I inhibition may decrease the generation of RET mediated “deleterious” ROS and could mediate the generation of “signaling” ROS at complex III. Whereas, during oxidation of complex I substrate pyruvate/malate (PM), VA-induced complex I inhibition could mediate generation of “signaling” ROS at complex I. VA-induced complex I and complex III inhibition may mediate slower rates of proton and electron transfer to reduce ATP synthesis during ischemia to preserve it during reperfusion. Possible modulating effects of VA on uncoupling protein (UCP) in promoting proton leak and uncoupling in cardioprotection are also noted. Other abbreviations: ANT, adenine nucleotide translocase; TCA cycle, tricarboxylic acid cycle; IMS, inter mitochondrial space.