Mitochondrial intermembrane junctional complexes and their role in cell death

Abstract

A mitochondrial complex comprising the voltage-dependent anion channel (outer membrane), the adenine nucleotide translocase (inner membrane) and cyclophilin-D (matrix) assembles at contact sites between the inner and outer membranes. Under pathological conditions associated with ischaemia and reperfusion the junctional complex 'deforms' into the permeability transition (PT) pore, which can open transiently, allowing free permeation of low Mr solutes across the inner membrane. This may be a critical step in the pathogenesis of lethal cell injury in ischaemia and reperfusion. Moreover, it is argued, the degree of pore opening may be an important determinant of the relative extent of apoptosis and necrosis under these conditions. In addition, mitochondria are the major sites of action of Bax and other apoptotic regulatory proteins of the Bcl-2 family. These proteins control a mitochondrial amplificatory loop in the apoptotic signalling pathway in which cytochrome c and other apoptogenic proteins of the mitochondrial intermembrane space are released into the cytosol. There are indications that the junctional complex, or components of it, may also mediate the action of Bax, but in a way that does not involve PT pore formation.

Figure 1. VDAC-ANT complexes

VDAC and ANT bind to each other and to a number of other proteins. These may, or may not, include Bax (see text). Under pathological conditions associated with ischaemia, the VDAC-ANT-CyP-D complex can deform into the PT pore, by which the inner membrane becomes permeabilized to low M_r solutes.

Figure 2. A model for the involvement of the PT pore in necrotic and apoptotic cell death during ischaemia and reperfusion

Ischaemia leads to ATP dissipation, with consequent rises in cell Ca²⁺ and P_i. On reperfusion, these three factors, together with oxidative stress, trigger PT pore opening. If widespread, PT pore opening overwhelms the ATP-generating capacity of the cell, and the cells become necrotic. If PT pore opening is more limited, enabling the cell to maintain sufficient ATP for viability, then outer membrane rupture may spark a caspase cascade, leading to apoptotis. The degree of PT pore opening may determine the balance between necrotic and apoptotic cell death.

Figure 3. The mitochondrial amplificatory loop

Mitochondria can be recruited into the apoptotic signalling pathway by Bid and Bax, which translocate from the cytosol to the mitochondrial outer membrane under apoptotic stimuli. Bid translocates as a truncated form (t-Bid) after cleavage by caspase-8. Bax is processed on the outer membrane to an active form (Bax*), a process possibly facilitated by t-Bid. Bax induces the release of apoptosis-inducing factor (AIF), procaspase-9, cytochrome c (cyt c) and other intermembrane space proteins to the cytosol. Cytochrome c binds to the adaptor protein Apaf-1, which is then able to bind procaspase-9 and -8, which are thus cleaved to their active forms.