The therapeutic potential of mitochondrial channels in cancer, ischemia-reperfusion injury, and neurodegeneration

Abstract

Mitochondria communicate with the rest of the cell through channels located in their inner and outer membranes. Most of the time, the message is encoded by the flow of anions and cations e.g., through VDAC and PTP, respectively. However, proteins are also both imported and exported across the mitochondrial membranes e.g., through TOM and MAC, respectively. Transport through mitochondrial channels is exquisitely regulated and controls a myriad of processes; from energy production to cell death. Here, we examine the role of some of the mitochondrial channels involved in neurodegeneration, ischemia-reperfusion injury and cancer in the context of their potential as therapeutic targets.

Figure 1. Mitochondrial ion channels

The mitochondrial channels MAC, PTP, VDAC, TIM (TIM22 and TIM23), and TOM are represented. MAC and PTP are mainly associated with release of mitochondrial death signals and induction of apoptosis in numerous cell types. While MAC specifically forms and opens in the outer membrane to release death factors (red spheres), PTP opening in the inner membrane results in matrix swelling and disruption of the outer membrane, which spills these factors into the cytosol. Turning on or off either channel could induce or prevent cell death respectively in different therapeutic approaches.

Figure 2. MAC activity can be turned on or off to induce or prevent apoptosis

A. Phase contrast microscopic image illustrates patch clamping of a mitochondrion (arrowhead). tBid is typically included inside the patch pipette to activate MAC, whereas iMACs are perfused into the bath to inhibit MAC. Scale bar is 2µm. B, C.. MAC activities were recorded in patches excised from mitochondria of mouse embryonic fibroblasts in presence of tBid (B) or from proteoliposomes containing mitochondrial outer membranes of apoptotic FL5.12 cells (C). Top current traces at +40 mV show inclusion of tBid in the patch pipette induced stepwise increase of MAC conductance. Bottom current traces at +20 mV show perfusion with buffer containing 25 nM iMAC2 induces stepwise blockade of MAC. Diagrams above current traces represent progressive pore assembly or disassembly by changing the number of helices in the pores (gray circles) (Martinez-Caballero et al., 2009) in presence of tBid or iMAC2, respectively. Dashed lines are 0 pA at 0 mV.