Mitochondrial ion channels as therapeutic targets

Abstract

The study of mitochondrial ion channels changed our perception of these double-wrapped organelles from being just the power house of a cell to the guardian of a cell's fate. Mitochondria communicate with the cell through these special channels. Most of the time, the message is encoded by ion flow across the mitochondrial outer and inner membranes. Potassium, sodium, calcium, protons, nucleotides, and proteins traverse the mitochondrial membranes in an exquisitely regulated manner to control a myriad of processes, from respiration and mitochondrial morphology to cell proliferation and cell death. This review is an update on both well established and putative mitochondrial channels regarding their composition, function, regulation, and therapeutic potential.

Figure 1. The main channel activities of mitochondrial membranes

Current traces were recorded from patches excised from either reconstituted or native membranes under symmetrical 150 mM KCl (see original articles). Pipette voltages vary from +5 to + 40 mV, but current traces are represented in the same scale for comparison. All the traces show open channels (o) with downward transitions to sub open and closed (c) states. Traces were adapted from [100] (mouse MAC, TOM and VDAC), [101] (human TIM23 and mCS), [60] (yeast TIM22), and [102] (mouse PTP).

Figure 2. Mitochondrial ion channels in apoptosis

Left, Apoptotic stimuli induce relocation of Bax from the cytosol into the mitochondrial outer membrane (MOM). Bax, Bak and possibly other unidentified protein(s) oligomerize and form MAC. An increase in ROS production, possibly due to Ca²⁺ entry through VDAC, MCU and mRyR, detaches cytochrome c from cardiolipin in the inner membrane (MIM). Cytochrome c spills into the cytoplasm and binds Apaf-1 to form apoptosomes and amplify the apoptotic cascade. Right, Necrotic stimuli lead to exacerbated Ca²⁺ uptake and ROS generation by mitochondria. High levels of Ca²⁺ and ROS induce a cyclophilin D (Cyp D)-sensitive opening of PTP that leads to swelling of the matrix and release of Ca²⁺. Swelling disrupts the outer membrane while released Ca²⁺ activates proteases, phosphatases and nucleases that lead to necrotic degradation.

Figure 3. Mitochondrial ion channels in protein import

The three major protein import complexes TOM, TIM23, and TIM22 are represented. Numbers indicate molecular weights of subunits and arrows indicate sorting pathways of mitochondrial proteins according to their targeting sequence. The detailed pathway, additional routes and components are reviewed in [54]. The three complexes rely on ion channels for protein import into mitochondria. In the outer membrane (MOM), Tom40 forms the channel of TOM. In the inner membrane (MIM), Tim23 and Tim17 form the channel of TIM23, while Tim22 forms the channel of the TIM22 complex.