Mitochondrial ion channels/transporters as sensors and regulators of cellular redox signaling

Abstract

Significance: Mitochondrial ion channels/transporters and the electron transport chain (ETC) serve as key sensors and regulators for cellular redox signaling, the production of reactive oxygen species (ROS) and nitrogen species (RNS) in mitochondria, and balancing cell survival and death. Although the functional and pharmacological characteristics of mitochondrial ion transport mechanisms have been extensively studied for several decades, the majority of the molecular identities that are responsible for these channels/transporters have remained a mystery until very recently.

Recent advances: Recent breakthrough studies uncovered the molecular identities of the diverse array of major mitochondrial ion channels/transporters, including the mitochondrial Ca2+ uniporter pore, mitochondrial permeability transition pore, and mitochondrial ATP-sensitive K+ channel. This new information enables us to form detailed molecular and functional characterizations of mitochondrial ion channels/transporters and their roles in mitochondrial redox signaling.

Critical issues: Redox-mediated post-translational modifications of mitochondrial ion channels/transporters and ETC serve as key mechanisms for the spatiotemporal control of mitochondrial ROS/RNS generation.

Future directions: Identification of detailed molecular mechanisms for redox-mediated regulation of mitochondrial ion channels will enable us to find novel therapeutic targets for many diseases that are associated with cellular redox signaling and mitochondrial ion channels/transporters.

FIG. 1.

Overview of mitochondrial ion channels/transporters and redox signaling. Under physiological conditions, the balance of mitochondrial ROS/RNS is tightly controlled by multiple mitochondrial ion channels/transporters that are located at the IMM and the OMM (OMM structure is abbreviated in this figure). In pathophysiological conditions, plasma membrane receptor (orange) stimulation, extracellular Ca²⁺ elevation, and/or exogenous ROS/RNS elevation (pink burst) trigger cellular signal transduction via kinase cascades, cytosolic Ca²⁺ elevation, and cytosolic ROS/RNS generation. These are amplified through reciprocal action (pink triangle) and transmit into mitochondria through redox-dependent PTMs of mitochondrial ion channels/transporters, especially Ca²⁺ channels at the IMM (blue). Mitochondrial Ca²⁺ efflux is mainly regulated by an mNCE. The PTM s of mitochondrial ion channels/transporters change the activity of the Ca²⁺ influx mechanism at IMM and induce Ca²⁺ accumulation into the mitochondrial matrix, which affects the efficiency of electron flow, ATP production, and O₂⁻ generation at ETC. The produced O₂⁻ reacts with other molecules (also each other) and forms additional ROS. The existence of mtNOS and the production of NO in matrix are still controversial. The excessive ROS/RNS in mitochondria are released into the cytosol through specific mitochondrial ion channels/transporters such as the mPTP (green) and the IMAC (not shown in the figure). IMM, inner mitochondrial membrane; OMM, outer mitochondrial membrane; mNCE, mitochondrial Na⁺/Ca²⁺ exchanger; mPTP, mitochondrial permeability transition pore; IMAC, inner membrane anion channel; ETC, electron transport chain; mtNOS, mitochondrial nitric oxide synthase; O₂⁻, superoxide; PTM, post-translational modification; ROS, reactive oxygen species; RNS, reactive nitrogen species. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 2.

Mitochondrial ETC and mitochondrial ROS generation. In a healthy eukaryotic cell, mitochondria generate more than 90% of the total intracellular ATP through the TCA cycle (green area) and OXPHOS (pink area). During OXPHOS, O₂⁻ is continuously produced as a primary oxygen free radical in mitochondria. NADH is produced from cytosolic glucose oxidation and the TCA cycle and passes electrons to NADH dehydrogenase (complex I). Then, complex I transfers electrons to CoQ10. CoQ10 can also receive electrons from succinate (complex II) and glycerol-3-phosphate dehydrogenase (NAD⁺). Electrons from reduced CoQ10 are then transferred to cytC oxidoreductase (complex III). Next, complex III transfers the electrons to cytC and the electron transport continues COX (complex IV) and molecular oxygen. Electron transfer processes through complexes I, III, and IV produce Δp, which, in turn, are used to drive ATP synthase (complex V). When Δp increases, electron transport in complex III is partially inhibited and results in an increased backup of electrons to CoQ10 for binding to molecular oxygen, leading to the generation of O₂⁻. In addition, when the electron-transport efficiency at complex I is suddenly inhibited or complex I activity is changed, this mechanism also generates O₂⁻. Red “explosion” symbols indicate places where O₂⁻ production occurs. Yellow star symbols indicate enzymes/channels that are regulated by [Ca²⁺]_mt. ETF-QO, electron transferring flavoprotein-quinone oxidoreductase; UCP, uncoupling protein; ANT, adenine nucleotide translocase; PDH, pyruvate dehydrogenase; CS, citrate synthase; ACON, aconitase; ICDH, isocitrate dehydrogenase; α-KDH, α-ketoglutarate dehydrogenase; SCS, succinyl-CoA synthetase; SDH, succinate dehydrogenase; FUM, fumarase; MDH, malate dehydrogenase; TCA, tricarboxylic acid; OXPHOS, oxidative phosphorylation; [Ca²⁺]_mt, mitochondrial matrix Ca²⁺ concentration; CoQ10, coenzyme Q10; COX, cytochrome c oxidase; cytC, cytochrome C. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 3.

Regulation of ETC activity by mitochondrial NO signaling. The existence of mtNOS and the production of NO in matrix are still controversial (see Introduction, Overview: Mitochondrial Ion Channels/Transporters, ETC, and Mitochondrial Redox Signaling, Regulation of ETC activity by mitochondrial NO signaling, and Interaction of NO, mitochondrial Ca²⁺, and ROS generation sections). NO diffused from cytosol to matrix or produced in mitochondrial matrix by mtNOS can reversibly interact with (complex IV) in competition with oxygen. NO inhibits the electron flow between cytochrome b and cytC at complex III. NADH dehydrogenase (complex I) receives S-nitrosylation (red circle), which shows reversible inhibition of complex I activity. Therefore, mitochondrial NO interferes with ETC activity (electron flow), and excessive mitochondrial NO production results in a decrease of ATP production, depolarization of ΔΨ_m and an increase in ROS generation. There are several reports showing that this tight functional coupling of NO and complex I or IV is derived from the physical interaction between mtNOS and complex I or IV. Complex I, NADH dehydrogenase; complex II, SDH; complex III, cytochrome bc₁ complex; complex IV, COX; complex V, ATP synthase; ΔΨ_m, mitochondrial membrane potential. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 4.

Redox-dependent PTMs. The redox-dependent PTMs are shown. These include cysteine and methionine oxidation (A, D), cysteine S-glutathionylation (A), cysteine disulfide bonds (B), cysteine surhydration (C), cysteine S-nitorosylation (C), tyrosine 3-nitration (E), and dityrosine formation (E). GSH, glutathione; GSSG, glutathione disulfide; GSNO, S-nitrosoglutathione; H₂S, hydrogen sulfide. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 5.

ROS-dependent regulation of cellular Ca²⁺ handing and ROS-induced ROS generation. Schematic diagram of ROS-dependent regulation of cellular Ca²⁺ handing and ROS-induced ROS generation. OMM structure is abbreviated in this figure. Red channels/transporters can be activated by the redox-dependent PTM. Gray channels/transporters can be inhibited by the redox-dependent PTMs. The redox modulations of white channels/transporters are unknown (no report) or still controversial. Voltage-gated Ca²⁺ channels (Cav) at the plasma membrane are phosphorylated by redox-dependent kinases and activated. RyR and IP₃R at SR/ER are activated by redox-dependent PTMs, which increase Ca²⁺ release from SR/ER. SERCA inhibited by irreversible oxidative modifications. PMCA is inhibited by either direct or indirect redox-dependent modifications. Thus, redox signaling generally increases cytosolic [Ca²⁺]_c. This [Ca²⁺]_c elevation feedbacks to mitochondria through an increase in the Ca²⁺ influx to mitochondrial matrix, which results in a positive feedback loop of ROS-induced ROS generation. mRyR1 and MCU, which are responsible for mitochondrial Ca²⁺ influx mechanism, are capable of receiving redox-dependent modulation. Excessive ROS/RNS are released through mPTP or IMAC (not shown in this figure) to the cytosol. Mitochondrial Ca²⁺ efflux is mainly regulated by an mNCE. During chronic heart failure, elevation of cytosolic [Na²⁺]_c accelerates mitochondrial Ca²⁺ efflux by mNCE and blunted [Ca²⁺]_mt accumulation, followed by an increase in the mitochondrial ROS level through the reduction of the NADPH-dependent antioxdative capacity at the matrix to control the mitochondrial H₂O₂ level. Thus, elevated [Na⁺]_c and mNCE activity also contributes to the regulation of [Ca²⁺]_mt homeostasis and ROS production, especially during chronic heart failure (see detailed in Mitochondrial Ca²⁺ Influx Mechanism and Mitochondrial ROS Generation section). PMCA, plasma membrane Ca²⁺ ATPase; RaM, rapid mode of uptake; LETM1, leucine zipper-EF-hand containing transmembrane protein 1; NCX, Na⁺/Ca²⁺ exchanger at plasma membrane; SR/ER, sarco/endoplasmic reticulum; SERCA, SR/ER Ca²⁺-ATPase; [Ca²⁺]_c, cytosolic Ca²⁺ concentration; [Na²⁺]_c, Na²⁺ concentration; H₂O₂, hydrogen peroxide; MCU, mitochondrial Ca²⁺ uniporter pore; NADPH, nicotinamide adenine dinucleotide phosphate; RyR, ryanodine receptor; mRyR1, mitochondrial ryanodine receptor type 1; IP₃R, IP₃ receptors. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 6.

Ca²⁺- and redox-dependent regulation of mPTP. A hypothetical model of mPTP structure is shown at the middle (red dot line area). CypD and ANT are currently recognized as regulatory proteins of mPTP. CypD and ANT receive redox-dependent PTMs (red circles). CypD, cyclophilin D. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars