Is mPTP the gatekeeper for necrosis, apoptosis, or both?

Abstract

Permeabilization of the mitochondrial membranes is a crucial step in apoptosis and necrosis. This phenomenon allows the release of mitochondrial death factors, which trigger or facilitate different signaling cascades ultimately causing the execution of the cell. The mitochondrial permeability transition pore (mPTP) has long been known as one of the main regulators of mitochondria during cell death. mPTP opening can lead to matrix swelling, subsequent rupture of the outer membrane, and a nonspecific release of intermembrane space proteins into the cytosol. While mPTP was purportedly associated with early apoptosis, recent observations suggest that mitochondrial permeabilization mediated by mPTP is generally more closely linked to events of late apoptosis and necrosis. Mechanisms of mitochondrial membrane permeabilization during cell death, involving three different mitochondrial channels, have been postulated. These include the mPTP in the inner membrane, and the mitochondrial apoptosis-induced channel (MAC) and voltage-dependent anion-selective channel (VDAC) in the outer membrane. New developments on mPTP structure and function, and the involvement of mPTP, MAC, and VDAC in permeabilization of mitochondrial membranes during cell death are explored. This article is part of a Special Issue entitled Mitochondria: the deadly organelle.

Figure 1. Mitochondrial ion channels in apoptosis and necrosis

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 to release cytochrome c. VDAC oligomerization upon apoptotic stimuli was also reported to be involved in cytochrome c release. Right, Necrotic stimuli lead to exacerbated calcium uptake and reactive oxygen species generation by mitochondria. High levels of calcium and reactive oxygen species (ROS) induce a cyclophilin-D (Cyp D)-sensitive opening of mPTP that leads to swelling of the matrix and release of calcium. Swelling disrupts the outer membrane while released calcium activates proteases, phosphatases and nucleases that lead to necrotic degradation. Adapted from [112]. TIM23/22, translocase of the inner membrane complexes 23/22; mRyR, mitochondrial ryanodine receptor; TOM, translocase of the outer membrane; MCU, mitochondrial calcium uniporter; MIM, mitochondrial inner membrane.

Figure 2. The channel activities of VDAC, mPTP and MAC

Current traces were recorded from patches excised from either reconstituted outer (MAC and VDAC) or native inner membranes (mPTP) under symmetrical 150 mM KCl. Current traces are represented in the same scale for comparison. Current levels of open (O) channels are shown with downward transitions to closed (C) states in all the traces. Mouse MAC and VDAC traces were adapted from ref. [62], while mouse mPTP was from ref. [56].

Figure 3. Crosstalk between MAC and mPTP amplifies cell death by apoptosis and necrosis

Elevated cytosolic Ca²⁺ activates calpain and calcineurin, which facilitate MAC formation through activation of Bid, Bad and Bax. Mitochondrial calcium overload in the matrix induces mPTP opening. Cytochrome c released after either MAC formation or mPTP opening facilitates apoptosome formation and caspase activation. Released cytochrome c causes further dysregulation of calcium homeostasis by interacting with the ER calcium release channel IP₃ receptors (IP₃R). Anti-apoptotic Bcl-2 suppresses while ROS signaling enhances the formation/activation of MAC, mPTP, and IP₃R. Thus, opening of MAC/mPTP, cytochrome c release, and activation of IP₃R may form a positive feedback loop to amplify the cell death signal. ER and MITO indicate endoplasmic reticulum and mitochondria, respectively. Adapted from [3].