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Review
, 20, 303-15

Mitochondrial Ion Channels: Gatekeepers of Life and Death

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Review

Mitochondrial Ion Channels: Gatekeepers of Life and Death

Brian O'Rourke et al. Physiology (Bethesda).

Abstract

Continuous generation of ATP by mitochondrial oxidative phosphorylation is essential to maintain function in mechanically active cells such as cardiomyocytes. Emerging evidence indicates that mitochondrial ion channels activated by reactive oxygen species can induce a mitochondrial "critical" state, which can scale to cause electrical and contractile dysfunction of the cardiac cell and, ultimately, the whole heart. Here we focus on how mitochondrial ion channels participate in life-and-death decisions of the cell and discuss the challenges ahead for translating recent findings into novel therapeutic applications.

Figures

Figure 1
Figure 1. Overview of oxidative phosphorylation in the cardiac cell
The sequential oxidation of fuels (e.g., fatty acids and glucose) leads to the common substrate for the Krebs cycle, acetyl-CoA, which drives the production of the reducing equivalents NADH and FADH2. Electrons are passed to the electron-transport chain, where coupled redox reactions mediate proton translocation across the inner membrane to establish an electrical potential and pH gradient (proton-motive force) that drives ATP synthesis by the mitochondrial ATP synthase. Ion-selective or nonselective mitochondrial ion channels dissipate energy and alter the ionic balance and volume of the mitochondrial matrix, which is partly compensated by antiporters coupled to H+ movement. See text for further details. ANT, adenine nucleotide translocase; G-6-P, glucose-6-phosphate; IMAC, inner-membrane anion channel; MCU, mitochondrial Ca2+ uniporter; mitoKCa, mitochondrial Ca2+-activated K+ channel; mitoKATP, mitochondrial ATP-sensitive K+ channel; PIC, phosphate carrier; PTP, permeability transition pore; PYR, pyruvate; KHE, K+/H+ exchanger; NHE, Na+/H+ exchanger; NCE, Na+/Ca2+ exchanger; IDH, isocitrate dehydrogenase; KDH, α-ketoglutarate dehydrogenase; MDH, malate dehydrogenase; PDH, pyruvate dehydrogenase; SDH, succinate dehydrogenase.
Figure 2
Figure 2. Possible sites of mitochondrial superoxide production
Superoxide (O2) can be produced as a byproduct of oxidative phosphorylation at several sites in the electron transport chain, including complex I (NADH dehydrogenase) and the Q-cycle of complex III (cytochrome bc1). Specific metabolic poisons can help to discriminate which sites are physiologically relevant. UQ, ubiquinone; UQ., ubisemiquinone; UQH2, ubiquinol.
Figure 3
Figure 3. Sequelae of ischemia and reperfusion
Loss of electrical and contractile function of the heart occurs rapidly after the onset of ischemia. Changes in intracellular ions and high-energy phosphates occur throughout the ischemic period, contributing to injury upon reperfusion. The time course of mitochondrial membrane potential (Δψm) depolarization is not well defined, but failure to recover Δψm upon reperfusion is likely to be the main determinant of cellular life or death. A burst of reactive oxygen species (ROS) and cellular and mitochondrial Ca2+ overload is known to occur within the first 5 min of reperfusion. SarckATP, sarcolemmal KATP channel; pCr, phosphocreatine.
Figure 4
Figure 4. Protective and destructive mitochondrial ion channels participating in the life-and-death decisions of the cell
Activation of either of two protective mitochondrial K+channels (mitoKATP and mitoKCa) has been shown to protect the heart against ischemia and reperfusion injury, whereas the opening of the PTP or the IMAC can result in the collapse (or oscillation in the case of the latter) of Δψm. The protective channels are known to inhibit PTP opening. This could occur either as a result of inhibition of the factors that cause PTP opening (e.g., ROS, Ca2+) or perhaps by direct physical interaction with the PTP protein complex.
Figure 5
Figure 5. Critical behavior of the mitochondrial network induced by oxidative stress
A: images of Δψm in an isolated guinea pig cardiomy-ocyte before local mitochondrial oxidative stress (left), after local Δψm depolarization, but before whole-cell depolarization of the mitochondrial network (middle; note square region of low Δψm), and during global depolarization (right). B: approach to mitochondrial criticality depends on the history of oxidative stress in the mitochondrial matrix, reported by the oxidation of the mitochondrially located fluorophore, chloro-methyl dichlorofluorescein (CM-DCF). When a significant fraction (∼60%) of the network shows evidence of elevated ROS production, a small further perturbation can lead to the catastrophic cell-wide depolarization of Δψm (image sequence corresponds to the same time points for the images shown in A). C: time course of whole-cell Δψm oscillation triggered by the local oxidative stress (red trace) and ROS production (indicated by the rate of change of the CM-DCF signal shown in green). Experiment was carried out as described in Aon et al. (3) using two-photon laser scanning fluorescence imaging. D: the mitochondrial oscillator, as previously described in the computational modeling study of Cortassa et al. (22). SOD, superoxide dismutase; GPX, glutathione peroxidase; CAT, catalase.
Figure 6
Figure 6. Scaling from the level of the organelle to the organ

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