Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Is MAC the knife that cuts cytochrome c from mitochondria during apoptosis?


Apoptosis is a phenomenon fundamental to higher eukaryotes and essential to mechanisms controlling tissue homeostasis. Bcl-2 family proteins tightly control this cell death program by regulating the permeabilization of the mitochondrial outer membrane and, hence, the release of cytochrome c and other proapoptotic factors. Mitochondrial apoptosis-induced channel (MAC) is the mitochondrial apoptosis-induced channel and is responsible for cytochrome c release early in apoptosis. MAC activity is detected by patch clamping mitochondria at the time of cytochrome c release. The Bcl-2 family proteins regulate apoptosis by controlling the formation of MAC. Depending on cell type and apoptotic inducer, Bax and/or Bak are structural component(s) of MAC. Overexpression of the antiapoptotic protein Bcl-2 eliminates MAC activity. The focus of this review is a biophysical characterization of MAC activity and its regulation by Bcl-2 family proteins, and ends with some discussion of therapeutic targets.


Apoptosis is a conserved cell death mechanism essential for normal development and tissue homeostasis in multicellular organisms (reviewed in Danial and Korsmeyer1, Antonsson2, Sharpe et al.3, Green and Kroemer4, Kuwana and Newmeyer5, Fadeel and Orrenius6, Lucken-Ardjomande and Martinou7, Martinez-Caballero et al.8 and Dejean et al.9). Two major signaling pathways leading to cell death by apoptosis have been identified. They are the extrinsic pathway (or the death receptor pathway) and the intrinsic pathway (or mitochondrial pathway). The extrinsic pathway involves the activation of receptors in the plasma membrane through the binding of ligands such as the Fas/CD95, TNFα and TRAIL.10 This receptor activation ultimately leads to processes that cleave and activate the initiator procaspases 8 and/or 10 which in turn activate the executioner caspases 3 and/or 7. The executioner caspases are responsible for the appearance of late apoptosis markers such as DNA fragmentation and plasma membrane blebbing.

Mitochondria play a pivotal role in the response of a variety of cell types to a diverse set of apoptotic signals that activate the intrinsic pathway, including DNA damage, growth factor withdrawal, and viral infection. Mitochondria release a number of factors from their intermembrane space, like cytochrome c, Smac/Diablo, and AIF, which promote and amplify the apoptotic cascade from the formation and activation of the apoptosomes to the final destruction of the cell.1, 2, 3, 6, 11 The Bcl-2 family of proteins is a key regulator of the mitochondrial response to apoptotic signals in the intrinsic pathway and contains both pro- and anti-apoptotic members (see other papers in this issue). Many of these proteins localize to mitochondria and finely control the process of apoptosis through regulation of the release of mitochondrial mediators of the apoptotic program into the cytosol (recently reviewed in Danial and Korsmeyer1, Antonsson2, Sharpe et al.3, Green and Kroemer4, Kuwana and Newmeyer5, Lucken-Ardjomande and Martinou7, Martinez-Caballero et al.8, Dejean et al.9, Juin et al.12). The extrinsic and intrinsic pathways initially appeared to be independent. However, it is now clear that a crosstalk exists between the two pathways that is mediated by the ‘BH3 domain-only’ proteins, for example Bid.13 In some cells, extrinsic caspase 8 cleaves Bid to form t-Bid, which facilitates Bax activation and oligomerization in mitochondria. Thus, t-Bid is generated by the extrinsic pathway and goes on to activate the intrinsic pathway.

The mechanisms responsible for the release of mitochondrial mediators of cell death are still a subject of lively discussion. It was first hypothesized that the opening of the permeability transition pore (PTP) of the inner membrane would cause swelling of the matrix space, which would rupture the outer membrane, and spill cytochrome c and other proapoptotic proteins into the cytosol.14, 15, 16 However, it was recently shown that sustained PTP opening is primarily involved in necrosis and ischemia–reperfusion.17, 18, 19 Cyclophilin-D is a regulator of the PTP. Remarkably, cyclophilin-D deficient cells died normally in response to apoptotic stimuli known to activate both the extrinsic and intrinsic pathways, but showed resistance to necrotic cell death induced by reactive oxygen species and Ca2+ overload.17 Furthermore, cytochrome c release can occur in the absence of mitochondrial depolarization and without loss of outer membrane integrity. These observations indicate that, instead of rupturing, a more selective mechanism of permeabilization is operating, like the formation of a pore in the outer membrane.11, 20, 21, 22, 23, 24

The mitochondrial apoptosis-induced channel (MAC), was detected by directly patch clamping mitochondria isolated from cells in early apoptosis. MAC activity is exquisitely regulated by Bcl-2 family proteins and can initiate release of apoptotic mediators from mitochondria to commit the cell to die.20, 23, 24 Nevertheless, MAC and PTP transient opening may act alone or in combination, depending on cell type and death stimulus, to relocalize Bax to the mitochondria, remodel the cristae, and maximize cytochrome c release to amplify the death signal.22, 25

The focus of this review is a biophysical characterization of MAC, cytochrome c permeability, and how Bcl-2 family proteins regulate the permeability of the mitochondrial outer membrane through the formation of MAC. We have also incorporated some personal notes regarding Stan Korsmeyer's contributions to our present understanding of MAC. Early in 1996, a call came into the lab from Stan. The loud commotion of the French Press in the lab made it nearly impossible to hear his exciting ideas about Bcl-2 family proteins and mitochondria. Needless to say, I then entered the field of apoptosis, a field in which Stan was a leading pioneer. This event began our many years of collaborations. Stan generously provided materials in which to expand our studies but also commitment and inspiration. For many years, this visionary scientist facilitated our work and that of so many other labs; he is sorely missed.

Electrophysiological Characterization of MAC

MAC was first detected in patch-clamp experiments on mitochondria isolated from apoptotic FL5.12 cells 12 h after interleukin-3 (IL-3) withdrawal.20 Stan actually provided this cell line and many of the protocols with which we began this study. Single-channel analysis of MAC was performed in proteoliposomes because the mitochondrial outer membrane is densely packed with voltage-dependent anion-selective channel (VDAC) and translocase of the outer membrane (TOM) channels. Proteoliposomes were formed with mitochondrial outer membranes purified from apoptotic and control cells (Figure 1a). Membrane patches were removed from the proteoliposomes with a micropipette and the current flow through the individual channels was characterized.

Figure 1
figure 1

MAC is a high conductance channel of the outer membrane permeable to up to 17 kDa polymers. (a) Immunoblots show the presence of the outer membrane protein VDAC but not the inner membrane protein cytochrome oxidase subunit IV (CoxIV) in the outer membranes (OM, 2 μg) purified from mitochondria of apoptotic FL5.12 cells. Inner membranes (IM, 2 μg) are the positive control for CoxIV. (b and c) MAC activity was reconstituted by incorporating mitochondrial outer membranes of apoptotic FL5.12 cells into proteoliposomes. (b) Current traces at 20 mV allow comparisons of the single-channel behavior of MAC, VDAC, and TOM channels. O and C indicate open and closed state current levels, respectively. (c) The pore size of MAC was estimated by the polymer exclusion method. Current traces are shown of a 4 nS MAC after sequential perfusion of the bath with media containing 5% w/vol of indicated MW dextrans as the voltage was switched between ±20 mV. 10 and 17 kDa MW dextrans are permeant as they induce a decrease in the current, but 45 and 71 kDa polymers are not. Parts of this figure were reprinted from Pavlov et al.,20 Guo et al.,23 and Martinez-Caballero et al.29

MAC is a heterogeneous high-conductance channel. There are multiple subconductance levels and MAC has transitions of up to 2.5 nS (Figure 1b). Although flickering between conductance states is sometimes observed, current traces usually show MAC occupying a stable open conductance state with relatively infrequent transitions.20, 23, 24 The activity of MAC is significantly different from the constitutive channels of the mitochondrial outer membrane, TOM and VDAC. The single-channel parameters of peak conductance, transition size, selectivity, and voltage dependence for these channels are in Table 1 and illustrated by the current traces of Figure 1. Note that the conductance of VDAC was 0.68±0.09 nS in 0.15 M KCl media in these studies,.20 which approximates the 4 nS typically reported by others in higher ionic strength (1 M KCl) media.26, 27, 28

Table 1 Comparison of the properties of mitochondrial outer membrane and BaxΔC20 channels while patch clamping proteoliposomesa

The conductance of MAC is both variable and high.23, 24 The mean conductance of MAC of apoptotic HeLa and FL5.12 cells is 3.3 and 4.5 nS, respectively.20, 23, 24 MAC is typically a voltage-independent channel,20, 23, 24, 29 although it has also been reported to occupy less than peak conductances at higher potentials.30 The channel is slightly cation-selective, which is consistent with MAC's putative role in releasing the cationic protein cytochrome c from mitochondria early in apoptosis.

The polymer exclusion method was used to measure the pore size of MAC,23 as has been performed with other channels31, 32, 33, 34, 35 MAC with a conductance of 4 nS is permeable to 10 and 17 kDa, but not 45 and 71 kDa dextran, as there is no current decrease upon introduction of the larger polymers (shown in Figure 1c). The polymer exclusion method indicates that MAC with conductances between 1.5 and 5 nS have pore sizes of 2.9–7.6 nm, which should be large enough to allow the passage of 3 nm cytochrome c.36

Is MAC the Cytochrome c Release Channel?

Cytochrome c modifies the electrophysiological behavior of MAC in a manner consistent with entrance of cytochrome c into the pore (Figure 2).23, 24 Physiological concentrations (0.1–1 mM) of cytochrome c reduce the current flow through MAC with conductances between 1.5 and 4 nS.23, 37 However, the effects of cytochrome c are complex and are now classified as Type 1 and Type 2.

Figure 2
figure 2

Cytochrome c induces Type 1 and Type 2 effects on MAC activity. (a) Current traces at +20 mV of MAC in the absence (Control) and presence of 100 μM cytochrome c (Cyt c) show a decrease in current and increase in noise corresponding to a Type 1 effect. (b) Current–voltage relationship for MAC in the presence (+Cyt c) and absence (Control) of cytochrome c shows a decrease in current through MAC and increase in noise at bath positive potentials. (c) A current trace of MAC illustrates that while hemoglobin (Hgb) has no effect, cytochrome c (Cyt c) induces a rapid Type 2 reduction in MAC conductance. Spikes in the current trace are due to perfusion of the bath. Reprinted from Guo et al.23

A Type 1 response is a 4–50% decrease in the conductance that is voltage dependent, reversible, and associated with an increase in current noise (Figure 2a). Similarly, some neurotoxins and other fast blockers are not thought to traverse pores but can modify noise levels and decrease conductance presumably by binding to the open state of the pore.38, 39 However, the presence of cytochrome c in the pore would displace small ions, for example potassium, and hence decrease the amount of current through, or conductance of, the channel. Furthermore, the current noise increases as the driving force for cytochrome c translocation into the micropipette increases, that is with increased positive voltage (Figure 2b). These effects are comparable to those of translocated molecules on including ATP on VDAC and DNA on α-hemolysin.26, 27, 28, 40 Similar effects have also been found with putative translocation of maltodextrins through maltoporins and single ampicillin molecules moving through the general bacterial porin, OmpF (outer membrane protein F).41, 42 Thus, the Type 1 effect provides strong evidence that cytochrome c enters the pore of MAC and other data support the notion that MAC is the cytochrome c release channel (see below in this section). It is interesting that hemoglobin has no effect on MAC conductance, indicating this 32 kDa, heme-containing dimer does not permeate through 2–5 nS MAC (Figure 2b). In contrast, the cationic protein ribonuclease A (14 kDa) has the same effects as cytochrome c (12.5 kDa).23

The Type 2 effects of cytochrome c are a 50–90% reduction in conductance that is dose dependent and voltage independent (Figure 2c). This response likely corresponds to a destabilization of the open state of MAC and is not a simple ‘plug’ because extensive washing typically does not restore conductance of the open state. We speculate that binding sites for cytochrome c may exist in the structure of 2–4 nS MAC, which could block the passageway and may be important in synchronization of apoptotic events.

The hypothesis that MAC provides the pathway through the outer membrane for release of cytochrome c early in apoptosis is supported by a variety of observations. As described above, the Type 1 effect is consistent with a partitioning of cytochrome c into the pore of 1.5–4 nS MAC, which is an essential step of translocation. The pore size of MAC estimated by the polymer exclusion method and/or calculated from the peak conductance is sufficient to allow the passage of the 12.5 kDa cytochrome c. The onset of MAC activity coincides with cytochrome c release in several systems.20, 23, 24, 29, 43 The temporal association of MAC formation and cytochrome c release is consistent with biochemical findings. Specifically, proteoliposomes made from apoptotic membranes express MAC activity and fail to retain cytochrome c compared with proteoliposomes of control cells.20 Hence, cytochrome c permeability increases early in apoptosis when MAC activity is present. Finally, the effects of Bcl-2 family proteins on MAC activity described below also support the identification of MAC as the cytochrome c release channel and provide some answers to questions about the relationship between MAC and Bcl-2 family proteins that were posed to me by Stan more than 10 years ago. In particular, we determined that MAC is, at least in part, composed of Bax and/or Bak and that Bcl-2 blocks MAC formation. These findings unequivocally link cytochrome c release with MAC and indicate that MAC is responsible for cytochrome c release in the early stages of intrinsic apoptosis.

Channel-forming Properties of Bcl-2 Family Proteins

X-ray studies of antiapoptotic Bcl-xL deprived of its hydrophobic C-terminus revealed structural similarities with bacterial toxins capable of pore formation.44 This observation led to the notion that Bcl-2 family proteins could form channels, which was examined by several groups using planar bilayers and recombinant proteins. The principal results of these investigations are presented in Table 2.45, 46, 47, 48, 49

Table 2 Electrophysiological characteristics of some recombinant pro- and anti-apoptotic Bcl-2 family proteins in a planar bilayers systema

Surprisingly, both antiapoptotic and proapoptotic proteins have channel-forming activity in artificial lipid membranes. Typically, the channels formed are slightly cation-selective and voltage independent. Consistent with their homology with bacterial toxins, the activity of all these channels is enhanced at low pH.50 Unlike Bax and Bak, antiapoptotic Bcl-2 family proteins and t-Bid only form large-conductance channels when they are assayed or pre-inserted at low pH (Table 2).45, 48 Importantly, no channel activity has been detected that can be attributed to Bcl-2 in mitochondria of cells overexpressing this protein.20, 51 These observations raised questions concerning the physiological relevance of channels formed by the antiapoptotic and ‘BH3 domain-only’ members of the Bcl-2 family.

Recombinant Bax has channel activity that is remarkably similar to that of MAC. Although Bax monomers form channels that up to 1.6 nS, this conductance corresponds to a pore that is too narrow to allow passage of cytochrome c (Table 2).45, 46 However, oligomerization of Bax before insertion into planar bilayers allows for the formation of nonselective, voltage-independent channels that show a gradual increase in conductance up to 5.4 nS.52 The diameter estimated from the peak conductance of 5.4 nS for Bax channels is 5.5 nm, which should easily allow the passage of 3 nm cytochrome c.36 This discovery was recently confirmed in a study in which the channel-forming activity of oligomeric Bax was monitored by patch-clamp techniques (see Table 1).24 Like MAC, cytochrome c and RNAse A induce Type 1 and Type 2 effects in recombinant BaxΔC20 channels, while hemoglobin has no effect (see current traces and histograms of Figure 3).

Figure 3
figure 3

Cytochrome c induces Type 1 and Type 2 effects on BaxΔC20 channels. (a) A current trace of a BaxΔC20 channel before and after addition of 100 μM cytochrome c (Cyt c) shows reversal of the effects upon washing (perfusion to remove cytochrome c), like the Type 1 effect of cytochrome c on MAC in Figure 2. (b) A current trace of a BaxΔC20 channel shows a Type 2 effect of perfusing 100 μM cytochrome c into the bath. (c) Histograms show the conductance of MAC (open) and BaxΔC20 (filled) channels in the presence relative to the absence of 100 μM cytochrome c, 100 μM ribonuclease A, or 200 μM hemoglobin as indicated. The effects of 100 μM cytochrome c on VDAC, translocase outer membrane channels (TOM), and liposomes conductances are also shown. Mean±S.E. is shown and n is the number of independent determinations. Parts of this figure were reprinted from Guo et al.23 and Dejean et al.24

The budding yeast Saccharomyces cerevisiae is a powerful tool to understand the complexities of the function of Bcl-2 family members because the genome contains no homologs of Bcl-2 family proteins (reviewed in Priault et al.53). Importantly, heterologous expression of Bax induces cell death and cytochrome c release in yeast.54, 55 Independently, Stan and Stephen Manon (U. Bordeaux) provided us with yeast strains so that we could determine whether a MAC-like activity was associated with Bax expression in mitochondria. Patch-clamp studies of yeast mitochondria expressing human Bax (hBax) in a VDAC-less strain detected a novel channel activity, which again, was similar to MAC activity found in mitochondria of apoptotic cells (Table 1).8, 20, 24 This hBax channel activity displays a large peak conductance (3–4 nS), no voltage dependence, and a slight cation selectivity (Table 1). The peak conductance indicates a pore size greater than 4 nm, which should allow passage of cytochrome c. These studies beg the question: is Bax a component of MAC?

Regulation of MAC by the Proapoptotic BCL-2 Family Proteins

There is strong evidence that Bax plays a crucial role in MAC channel formation. First, MAC and recombinant oligomeric Bax channels have indistinguishable channel activities that are cytochrome c sensitive (Tables 1 and 2; Figures 2 and 3).24 MAC activity appears when Bax levels increase in mitochondria of apoptotic FL5.12 cells.20 MAC is also detected as an increase in outer membrane permeability by patch-clamp techniques in staurosporine-treated HeLa cells when Bax-GFP forms clusters in mitochondria and cytochrome c is released.24 Although correlative, this evidence supports a mechanistic link between Bax translocation and oligomerization, MAC formation, and cytochrome c release that is directly tested by the molecular and immunological studies described below.

Bax is a component of MAC of staurosporine-treated HeLa cells because MAC activity is depleted after immunoprecipitation of oligomeric Bax. In this system, MAC activity is present in total mitochondrial lysates and fractions containing oligomeric, but not monomeric, Bax (Figure 4).24 This is expected as Bax oligomers form in the outer membrane following Bax translocation to mitochondria at the time that cytochrome c is released.22, 24, 56, 57 Importantly, MAC activity is depleted from solubilized mitochondrial fractions by Bax antibodies raised against an N-terminal epitope of the protein (Figure 4).24 This epitope is inaccessible in monomeric Bax but becomes exposed following Bax activation. Thus, these antibodies selectively immunoprecipitate oligomeric Bax.58, 59 The concomitant loss of MAC activity and oligomeric Bax by immunoprecipitation indicates that Bax is a component of MAC.

Figure 4
figure 4

Bax and/or Bak are components of MAC. (a) Western blots show the presence of Bax in pellets (P) and supernatants (S) subjected to SDS-PAGE after immunoprecipitation of total mitochondrial lysates and fractions of HeLa cells containing oligomeric and monomeric Bax with anti-Bax antibodies (Bax Ab) or total rabbit IgG (control Ab). (b) The supernatants corresponding to immunoprecipitates with anti-Bax antibodies (Bax Ab, closed) or with total rabbit IgG (Control Ab, open) were reconstituted in proteoliposomes and MAC detection frequency was determined by patch clamping. N=20–23 independent patches/condition. P values were calculated using the Fisher exact statistical test. (c) Mitochondria were isolated from three MEF cell lines, Parental, single Bax KO, and Bax/Bak double KO (DKO) that were (STS) and were not (control) treated with staurosporine. The mean conductance of the outer membrane was measured by patch-clamping isolated mitochondria (N=20–23 patches per condition). (d) An ELISA assay was used to assess cytochrome c release in the supernatants after permeabilization of the cells with digitonin. Alamethicin (80 μg/ml) was added during digitonin treatment as a positive control for cytochrome c release using the method of Polster et al.70 Parts of this figure were modified from Dejean et al.24

Previous studies using single and double knockout cell lines for Bax and Bak found these two proteins are functionally redundant with respect to their role in apoptosis (see Danial and Korsmeyer1, Antonsson2, Sharpe et al.3, Green and Kroemer4 for a review). Stan generously provided us with these cell lines in order to determine the relationship between MAC and these two proapoptotic proteins using molecular approaches. Cytochrome c release occurs in Bax and Bak single knockout cells but not in the double Bax/Bak knockout cells during staurosporine treatment (Figure 4d).21, 24 Similarly, MAC is detected in single knockout, but not the double knockout cell lines during staurosporine treatment (Figure 4c). Although alternative interpretations are possible, and considering that Bax is a component of MAC of staurosporine-treated HeLa cells, these data support the notion that Bak may replace Bax as a structural component of MAC in Bax-deficient cells. That is, Bax and Bak are functionally redundant with respect to MAC.

During apoptosis, the ‘BH3 domain-only protein’ Bid is cleaved to form a C-terminal truncated form referred to as t-Bid. The fragment t-Bid triggers oligomerization of both Bax and Bak in the mitochondrial outer membrane, which causes cytochrome c release.60, 61 Furthermore, t-Bid can trigger oligomerization of recombinant monomeric Bax in artificial membranes.24, 52 The oligomerization results in formation of voltage independent and slightly cationic channels with conductances of 1.5–10 nS, which are detected by patch-clamp techniques.24 Moreover, cytochrome c is transported through these t-Bid induced Bax channels, which again makes them very similar to MAC.24 Future studies will determine whether t-Bid induces MAC activity in isolated mitochondria.

Regulation of MAC by the Antiapoptotic Proteins

Bcl-2 is one of the best studied antiapoptotic proteins in the Bcl-2 family1, 2, 3, 4, 5 and was a central theme of much of the work of the Korsmeyer group. Stan provided us with FL5.12 cell lines that did or did not overexpress antiapoptotic Bcl-2 or mutant Bcl-2 and suggested we determine the relationship between MAC and Bcl-2 family proteins (see below for further details). MAC has never been detected in IL-3-starved FL5.12 cells that overexpress Bcl-2.20 This result suggests that Bcl-2 can inhibit MAC formation. However, the molecular mechanisms of this inhibition are as yet poorly defined. Recombinant Bcl-2 can form channels in planar bilayers.45, 48 In contrast, no new channel activities are detected when Bcl-2 is overexpressed in FL5.12 or MDA-231 cells, suggesting that this protein does not form channels in native mitochondrial membranes.20, 51 However, channels whose conductance is between 0.75 and 1 nS are detected in isolated mitochondria after addition of caspase-cleaved recombinant Bcl-xL (ΔN-Bcl-xL).62 These channels have conductances and other properties similar to mitochondrial channels detected in squid giant synapses during early stages of hypoxia-mediated apoptosis, when Bcl-xL is cleaved by caspases.63 In particular, conductances were detected of up to 3.8 nS in media containing 570 mM KCl in the micropipette.63 For purposes of comparison, this peak conductance should correspond to about 1 nS in symmetrical 150 mM KCl. Hence, the pore size is expected to be too small to allow for cytochrome c transport through the outer membrane and therefore is unlikely to have the same role as MAC during early steps of the intrinsic apoptotic pathway.

Pharmacology of MAC/Bax Channels

MAC is a potential therapeutic target because of its role in the commitment step of apoptosis, that is, cytochrome c release. The pharmacological profile of MAC activity is still limited. However, dibucaine, propranolol and trifluoperazine have been identified in patch-clamp experiments as dose-dependent MAC inhibitors. The IC50 are 39, 52 and 1 μM for dibucaine, propranolol and trifluoperazine, respectively.29 In contrast, lidocaine, a structural homolog of dibucaine, has little effect on MAC. In addition, cyclosporine A, a well-known PTP blocker64, 65, 66 has no effect on MAC activity, which reinforces the notion that MAC and the PTP are independent.29 It has been shown that trifluoperazine and propranolol prevent apoptosis in some cell lines,67, 68 and trifluoperazine and dibucaine also block mitochondrial depolarization induced by glutamate in neurons.69 Dibucaine, trifluoperazine and propranolol also block cytochrome c release from mitochondria induced by recombinant Bax and ‘BH3 domain-only’ proteins like t-Bid.70 These studies provide yet another link between Bax and MAC.

Previously, Antonsson and colleagues71 identified several derivatives of 2-propanol that blocked cytochrome c release induced by t-Bid in isolated mitochondria; some have IC50 in the nanomolar range. Recently, two novel agents were found to block the channel activity of recombinant Bax in planar bilayers and inhibit release of cytochrome c induced by t-Bid.72 These drugs may be more specific than dibucaine, propranolol, and trifluoperazine, as they did not block apoptosis induced by staurosporine in cell lines deficient in Bax. Importantly, both agents were effective in blocking apoptosis of neurons in an animal model of global brain ischemia. Inhibition of MAC/Bax channel activity could be an efficient target to prevent apoptosis and therefore reduce tissue damage following ischemic injuries in the brain and presumably other tissues.72

Future Perspectives

As shown in the model of Figure 5, MAC is central to the commitment step of apoptosis. The formation of MAC can be triggered by the BH3 domain-only protein t-Bid and this event corresponds to an oligomerization of Bax and/or Bak. As predicted by Stan, MAC formation is prevented by overexpression of antiapoptotic Bcl-2. Once formed, MAC facilitates the release of cytochrome c, which initiates activation of executioner caspases and cell death. Hence, MAC is the ‘knife’ that cuts cytochrome c from mitochondria. It has been suggested that the oligomerization of Bax mediated by t-Bid is dependent on one or more mitochondrial proteins.73 Although oligomeric Bax has been shown to be a component of MAC, no endogenous proteins resident in the outer membrane are clearly implicated in the structure of MAC. Recent work by Youle, Jensen, Koehler, Scorrano and others has revealed a role for mitochondrial shape in apoptosis.74, 75, 76, 77, 78 In particular, mitochondria typically fragment during apoptosis and inhibition of fission blocks cell death. Are the fission and fusion proteins Drp1, Opa1 or endophilin B candidates for Bax partners? Interestingly, Youle and Karbowski75 hypothesize that BCL-2 family proteins control apoptosis by regulating the morphogenesis pathways of mitochondria (see also the reviews from RJ Youle and L Scorrano in this issue). The relationship between MAC activity and these pathways may be enlightening with regard to mechanisms of fission and fusion as well as cytochrome c release in apoptosis.

Figure 5
figure 5

MAC provides a pathway for cytochrome c to exit the mitochondria during apoptosis. Model shows that Bcl-2 family members play a critical role regulating MAC formation. Induction of the intrinsic pathway results in Bax translocation to mitochondria and oligomerization. The BH3 domain-only protein t-Bid facilitates activation and oligomerization of Bax and Bak to form MAC. The antiapoptotic protein Bcl-2 suppresses MAC formation. MAC could be predominantly composed of either Bax or Bak. There may be other components and Bax and Bak may or may not form hetero-oligomers. MAC formation results in the release of cytochrome c and ultimately apoptosome formation, caspase activation and cell death. Model was modified from Dejean et al.9



permeability transition pore


mitochondrial apoptosis-induced channel




voltage-dependent anion-selective channel


adenine nucleotide translocator


translocase of the outer membrane


  1. Danial NN and Korsmeyer SJ (2004) Cell death: critical control points. Cell 116: 205–219.

    CAS  PubMed  Google Scholar 

  2. Antonsson B (2004) Mitochondria and the Bcl-2 family proteins in apoptosis signaling pathways. Mol. Cell Biochem. 256–257: 141–155.

    PubMed  Article  Google Scholar 

  3. Sharpe JC, Arnoult D and Youle RJ (2004) Control of mitochondrial permeability by Bcl-2 family members. Biochim. Biophys. Acta 1644: 107–113.

    CAS  Article  PubMed  Google Scholar 

  4. Green DR and Kroemer G (2004) The pathophysiology of mitochondrial cell death. Science 305: 626–629.

    CAS  PubMed  Article  Google Scholar 

  5. Kuwana T and Newmeyer DD (2003) Bcl-2-family proteins and the role of mitochondria in apoptosis. Curr. Opin. Cell Biol. 15: 691–699.

    CAS  PubMed  Article  Google Scholar 

  6. Fadeel B and Orrenius S (2005) Apoptosis: a basic biological phenomenon with wide-ranging implications in human disease. J. Intern. Med. 258: 479–517.

    CAS  PubMed  Article  Google Scholar 

  7. Lucken-Ardjomande S and Martinou JC (2005) Regulation of Bcl-2 proteins and of the permeability of the outer mitochondrial membrane. C. R. Biol. 328: 616–631.

    CAS  PubMed  Article  Google Scholar 

  8. Martinez-Caballero S, Dejean LM, Jonas EA and Kinnally KW (2005) The role of the mitochondrial apoptosis induced channel MAC in cytochrome c release. J. Bioenerg. Biomembr. 37: 155–164.

    CAS  PubMed  Article  Google Scholar 

  9. Dejean LM, Martinez-Caballero S, Manon S and Kinnally KW (2006) Regulation of the mitochondrial apoptosis-induced channel, MAC, by BCL-2 family proteins. Biochim. Biophys. Acta 1762: 191–201.

    CAS  PubMed  Article  Google Scholar 

  10. Schmitz I, Kirchhoff S and Krammer PH (2000) Regulation of death receptor-mediated apoptosis pathways. Int. J. Biochem. Cell. Biol. 32: 1123–1136.

    CAS  PubMed  Article  Google Scholar 

  11. Liu X, Kim CN, Yang J, Jemmerson R and Wang X (1996) Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c. Cell 86: 147–157.

    CAS  Article  PubMed  Google Scholar 

  12. Juin P, Cartron PF and Vallette FM (2005) Activation of Bax by BH3 domains during apoptosis: the unfolding of a deadly plot. Cell Cycle 4: 637–642.

    CAS  PubMed  Article  Google Scholar 

  13. Li H, Zhu H, Xu CJ and Yuan J (1998) Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94: 491–501.

    CAS  Article  PubMed  Google Scholar 

  14. Kroemer G and Reed JC (2000) Mitochondrial control of cell death. Nat. Med. 6: 513–519.

    CAS  PubMed  Article  Google Scholar 

  15. Skulachev VP (1996) Why are mitochondria involved in apoptosis? Permeability transition pores and apoptosis as selective mechanisms to eliminate superoxide-producing mitochondria and cell. FEBS Lett. 397: 7–10.

    CAS  PubMed  Article  Google Scholar 

  16. Marzo I, Brenner C, Zamzami N, Susin SA, Beutner G, Brdiczka D, Remy R, Xie ZH, Reed JC and Kroemer G (1998) The permeability transition pore complex: a target for apoptosis regulation by caspases and bcl-2-related proteins. J. Exp. Med. 187: 1261–1271.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. Nakagawa T, Shimizu S, Watanabe T, Yamaguchi O, Otsu K, Yamagata H, Inohara H, Kubo T and Tsujimoto Y (2005) Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death. Nature 434: 652–658.

    CAS  PubMed  Article  Google Scholar 

  18. Baines CP, Kaiser RA, Purcell NH, Blair NS, Osinska H, Hambleton MA, Brunskill EW, Sayen MR, Gottlieb RA, Dorn GW, Robbins J and Molkentin JD (2005) Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature 434: 658–662.

    CAS  PubMed  Article  Google Scholar 

  19. Basso E, Fante L, Fowlkes J, Petronilli V, Forte MA and Bernardi P (2005) Properties of the permeability transition pore in mitochondria devoid of Cyclophilin D. J. Biol. Chem. 280: 18558–18561.

    CAS  PubMed  Article  Google Scholar 

  20. Pavlov EV, Priault M, Pietkiewicz D, Cheng EH, Antonsson B, Manon S, Korsmeyer SJ, Mannella CA and Kinnally KW (2001) A novel, high conductance channel of mitochondria linked to apoptosis in mammalian cells and Bax expression in yeast. J. Cell. Biol. 155: 725–731.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. Wei MC, Zong WX, Cheng EH, Lindsten T, Panoutsakopoulou V, Ross AJ, Roth KA, MacGregor GR, Thompson CB and Korsmeyer SJ (2001) Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 292: 727–730.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. De Giorgi F, Lartigue L, Bauer MK, Schubert A, Grimm S, Hanson GT, Remington SJ, Youle RJ and Ichas F (2002) The permeability transition pore signals apoptosis by directing Bax translocation and multimerization. FASEB J. 16: 607–609.

    CAS  PubMed  Article  Google Scholar 

  23. Guo L, Pietkiewicz D, Pavlov EV, Grigoriev SM, Kasianowicz JJ, Dejean LM, Korsmeyer SJ, Antonsson B and Kinnally KW (2004) Effects of cytochrome c on the mitochondrial apoptosis-induced channel MAC. Am .J. Physiol. Cell Physiol. 286: C1109–C1117.

    CAS  PubMed  Article  Google Scholar 

  24. Dejean LM, Martinez-Caballero S, Guo L, Hughes C, Teijido O, Ducret T, Ichas F, Korsmeyer SJ, Antonsson B, Jonas EA and Kinnally KW (2005) Oligomeric Bax is a component of the putative cytochrome c release channel MAC, mitochondrial apoptosis-induced channel. Mol. Biol. Cell. 16: 2424–2432.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. Scorrano L and Korsmeyer SJ (2003) Mechanisms of cytochrome c release by proapoptotic BCL-2 family members. Biochem. Biophys. Res. Commun. 304: 437–444.

    CAS  Article  PubMed  Google Scholar 

  26. Rostovtseva T and Colombini M (1997) VDAC channels mediate and gate the flow of ATP: implications for the regulation of mitochondrial function. Biophys. J. 72: 1954–1962.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. Rostovtseva TK and Bezrukov SM (1998) ATP transport through a single mitochondrial channel, VDAC, studied by current fluctuation analysis. Biophys. J. 74: 2365–2373.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. Rostovtseva TK, Komarov A, Bezrukov SM and Colombini M (2002) Dynamics of nucleotides in VDAC channels: structure-specific noise generation. Biophys. J. 82: 193–205.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. Martinez-Caballero S, Dejean LM and Kinnally KW (2004) Some amphiphilic cations block the mitochondrial apoptosis-induced channel, MAC. FEBS Lett. 568: 35–38.

    CAS  PubMed  Article  Google Scholar 

  30. Guihard G, Bellot G, Moreau C, Pradal G, Ferry N, Thomy R, Fichet P, Meflah K and Vallette FM (2004) The mitochondrial apoptosis-induced channel (MAC) corresponds to a late apoptotic event. J. Biol. Chem. 279: 46542–46550.

    CAS  PubMed  Article  Google Scholar 

  31. Truscott KN, Kovermann P, Geissler A, Merlin A, Meijer M, Driessen AJ, Rassow J, Pfanner N and Wagner R (2001) A presequence- and voltage-sensitive channel of the mitochondrial preprotein translocase formed by Tim23. Nat. Struct. Biol. 8: 1074–1082.

    CAS  PubMed  Article  Google Scholar 

  32. Krasilnikov OV, Sabirov RZ, Ternovsky VI, Merzliak PG and Muratkhodjaev JN (1992) A simple method for the determination of the pore radius of ion channels in planar lipid bilayer membranes. FEMS Microbiol. Immunol. 5: 93–100.

    CAS  PubMed  Article  Google Scholar 

  33. Krasilnikov OV, Da Cruz JB, Yuldasheva LN, Varanda WA and Nogueira RA (1998) A novel approach to study the geometry of the water lumen of ion channels: colicin Ia channels in planar lipid bilayers. J. Membr. Biol. 161: 83–92.

    CAS  PubMed  Article  Google Scholar 

  34. Grigoriev SM, Muro C, Dejean LM, Campo ML, Martinez-Caballero S and Kinnally KW (2004) Electrophysiological approaches to the study of protein translocation in mitochondria. Int. Rev. Cytol. 238: 227–274.

    CAS  PubMed  Article  Google Scholar 

  35. Bezrukov SM and Kasianowicz JJ (1997) The charge state of an ion channel controls neutral polymer entry into its pore. Eur. Biophys. J. 26: 471–476.

    CAS  PubMed  Article  Google Scholar 

  36. Chan SK, Tulloss I and Margoliash E (1966) Primary structure of the cytochrome c from the snapping turtle, Chelydra serpentina. Biochemistry 5: 2586–2597.

    CAS  PubMed  Article  Google Scholar 

  37. Gupte SS and Hackenbrock CR (1988) The role of cytochrome c diffusion in mitochondrial electron transport. J. Biol. Chem. 263: 5248–5253.

    CAS  PubMed  Google Scholar 

  38. Tang QY, Qi Z, Naruse K and Sokabe M (2003) Characterization of a functionally expressed stretch-activated BKca channel cloned from chick ventricular myocytes. J. Membr. Biol. 196: 185–200.

    CAS  PubMed  Article  Google Scholar 

  39. Moczydlowski E (1986) Single channel enzymology. In Ion Channel Reconstitution, Miller C (ed) (Plenum Press: New York, NY) pp. 75–113.

    Chapter  Google Scholar 

  40. Akeson M, Branton D, Kasianowicz JJ, Brandin E and Deamer DW (1999) Microsecond time-scale discrimination among polycytidylic acid, polyadenylic acid, and polyuridylic acid as homopolymers or as segments within single RNA molecules. Biophys. J. 77: 3227–3233.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. Kullman L, Winterhalter M and Bezrukov SM (2002) Transport of maltodextrins through maltoporin: a single-channel study. Biophys. J. 82: 803–812.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. Nestorovich EM, Danelon C, Winterhalter M and Bezrukov SM (2002) Designed to penetrate: time-resolved interaction of single antibiotic molecules with bacterial pores. Proc. Natl. Acad. Sci. USA 99: 9789–9794.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  43. Gross A, Jockel J, Wei MC and Korsmeyer SJ (1998) Enforced dimerization of BAX results in its translocation, mitochondrial dysfunction and apoptosis. EMBO J. 17: 3878–3885.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. Muchmore SW, Sattler M, Liang H, Meadows RP, Harlan JE, Yoon HS, Nettesheim D, Chang BS, Thompson CB, Wong SL, Ng SL and Fesik SW (1996) X-ray and NMR structure of human Bcl-xL, an inhibitor of programmed cell death. Nature 381: 335–341.

    CAS  Article  PubMed  Google Scholar 

  45. Schlesinger PH, Gross A, Yin XM, Yamamoto K, Saito M, Waksman G and Korsmeyer SJ (1997) Comparison of the ion channel characteristics of proapoptotic BAX and antiapoptotic BCL-2. Proc. Natl. Acad. Sci. USA 94: 11357–11362.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. Antonsson B, Conti F, Ciavatta A, Montessuit S, Lewis S, Martinou I, Bernasconi L, Bernard A, Mermod JJ, Mazzei G, Maundrell K, Gambale F, Sadoul R and Martinou JC (1997) Inhibition of Bax channel-forming activity by Bcl-2. Science 277: 370–372.

    CAS  Article  PubMed  Google Scholar 

  47. Minn AJ, Velez P, Schendel SL, Liang H, Muchmore SW, Fesik SW, Fill M and Thompson CB (1997) Bcl-x(L) forms an ion channel in synthetic lipid membranes. Nature 385: 353–357.

    CAS  PubMed  Article  Google Scholar 

  48. Schendel SL, Azimov R, Pawlowski K, Godzik A, Kagan BL and Reed JC (1999) Ion channel activity of the BH3 only Bcl-2 family member, BID. J. Biol. Chem. 274: 21932–21936.

    CAS  Article  PubMed  Google Scholar 

  49. Schendel SL, Xie Z, Montal MO, Matsuyama S, Montal M and Reed JC (1997) Channel formation by antiapoptotic protein Bcl-2. Proc. Natl. Acad. Sci. USA 94: 5113–5118.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. Stroud R (1995) Ion channel forming colicins. Curr. Opin. Struct. Biol. 5: 514–520.

    CAS  PubMed  Article  Google Scholar 

  51. Murphy RC, Schneider E and Kinnally KW (2001) Overexpression of Bcl-2 suppresses the calcium activation of a mitochondrial megachannel. FEBS Lett. 497: 73–76.

    CAS  PubMed  Article  Google Scholar 

  52. Roucou X, Rostovtseva T, Montessuit S, Martinou JC and Antonsson B (2002) Bid induces cytochrome c-impermeable Bax channels in liposomes. Biochem. J. 363: 547–552.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. Priault M, Camougrand N, Kinnally KW, Vallette FM and Manon S (2003) Yeast as a tool to study Bax/mitochondrial interactions in cell death. FEMS Yeast. Res. 4: 15–27.

    CAS  PubMed  Article  Google Scholar 

  54. Hanada M, Aime-Sempe C, Sato T and Reed JC (1995) Structure-function analysis of Bcl-2 protein. Identification of conserved domains important for homodimerization with Bcl-2 and heterodimerization with Bax. J. Biol. Chem. 270: 11962–11969.

    CAS  PubMed  Article  Google Scholar 

  55. Manon S, Chaudhuri B and Guerin M (1997) Release of cytochrome c and decrease of cytochrome c oxidase in Bax-expressing yeast cells, and prevention of these effects by coexpression of Bcl-xL. FEBS Lett. 415: 29–32.

    CAS  Article  PubMed  Google Scholar 

  56. Antonsson B, Montessuit S, Sanchez B and Martinou JC (2001) Bax is present as a high molecular weight oligomer/complex in the mitochondrial membrane of apoptotic cells. J. Biol. Chem. 276: 11615–11623.

    CAS  Article  PubMed  Google Scholar 

  57. Mikhailov V, Mikhailov M, Pulkrabek DJ, Dong Z, Venkatachalam MA and Saikumar P (2001) Bcl-2 prevents bax oligomerization in the mitochondrial outer membrane. J. Biol. Chem. 276: 18361–18374.

    CAS  PubMed  Article  Google Scholar 

  58. Nechushtan A, Smith CL, Hsu YT and Youle RJ (1999) Conformation of the Bax C-terminus regulates subcellular location and cell death. EMBO J. 18: 2330–2341.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. Desagher S, Osen-Sand A, Nichols A, Eskes R, Montessuit S, Lauper S, Maundrell K, Antonsson B and Martinou JC (1999) Bid-induced conformational change of Bax is responsible for mitochondrial cytochrome c release during apoptosis. J. Cell. Biol. 144: 891–901.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. Wei MC, Lindsten T, Mootha VK, Weiler S, Gross A, Ashiya M, Thompson CB and Korsmeyer SJ (2000) tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c. Genes Dev. 14: 2060–2071.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Eskes R, Desagher S, Antonsson B and Martinou JC (2000) Bid induces the oligomerization and insertion of Bax into the outer mitochondrial membrane. Mol. Cell. Biol. 20: 929–935.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. Jonas EA, Hickman JA, Chachar M, Polster BM, Brandt TA, Fannjiang Y, Ivanovska I, Basanez G, Kinnally KW, Zimmerberg J, Hardwick JM and Kaczmarek LK (2004) Proapoptotic N-truncated BCL-xL protein activates endogenous mitochondrial channels in living synaptic terminals. Proc. Natl. Acad. Sci. USA 101: 13590–13595.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  63. Jonas EA, Hickman JA, Hardwick JM and Kaczmarek LK (2005) Exposure to hypoxia rapidly induces mitochondrial channel activity within a living synapse. J. Biol. Chem. 280: 4491–4497.

    CAS  PubMed  Article  Google Scholar 

  64. Lenartowicz E, Bernardi P and Azzone GF (1991) Phenylarsine oxide induces the cyclosporin A-sensitive membrane permeability transition in rat liver mitochondria. J. Bioenerg. Biomembr. 23: 679–688.

    CAS  Article  PubMed  Google Scholar 

  65. Szabo I, Bernardi P and Zoratti M (1992) Modulation of the mitochondrial megachannel by divalent cations and protons. J. Biol. Chem. 267: 2940–2946.

    CAS  PubMed  Google Scholar 

  66. Broekemeier KM, Carpenter-Deyo L, Reed DJ and Pfeiffer DR (1992) Cyclosporin A protects hepatocytes subjected to high Ca2+ and oxidative stress. FEBS Lett. 304: 192–194.

    CAS  PubMed  Article  Google Scholar 

  67. Nieminen AL, Saylor AK, Tesfai SA, Herman B and Lemasters JJ (1995) Contribution of the mitochondrial permeability transition to lethal injury after exposure of hepatocytes to t-butylhydroperoxide. Biochem. J. 307 (Part 1): 99–106.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. Freedman AM, Kramer JH, Mak IT, Cassidy MM and Weglicki WB (1991) Propranolol preserves ultrastructure in adult cardiocytes exposed to anoxia/reoxygenation: a morphometric analysis. Free Radic. Biol. Med. 11: 197–206.

    CAS  PubMed  Article  Google Scholar 

  69. Hoyt KR, Sharma TA and Reynolds IJ (1997) Trifluoperazine and dibucaine-induced inhibition of glutamate-induced mitochondrial depolarization in rat cultured forebrain neurones. Br. J. Pharmacol. 122: 803–808.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. Polster BM, Basanez G, Young M, Suzuki M and Fiskum G (2003) Inhibition of Bax-induced cytochrome c release from neural cell and brain mitochondria by dibucaine and propranolol. J. Neurosci. 23: 2735–2743.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  71. Bombrun A, Gerber P, Casi G, Terradillos O, Antonsson B and Halazy S (2003) 3, 6-dibromocarbazole piperazine derivatives of 2-propanol as first inhibitors of cytochrome c release via Bax channel modulation. J. Med. Chem. 46: 4365–4368.

    CAS  PubMed  Article  Google Scholar 

  72. Hetz C, Vitte PA, Bombrun A, Rostovtseva TK, Montessuit S, Hiver A, Schwarz MK, Church DJ, Korsmeyer SJ, Martinou JC and Antonsson B (2005) Bax channel inhibitors prevent mitochondrion-mediated apoptosis and protect neurons in a model of global brain ischemia. J. Biol. Chem. 280: 42960–42970.

    CAS  PubMed  Article  Google Scholar 

  73. Roucou X, Montessuit S, Antonsson B and Martinou JC (2002) Bax oligomerization in mitochondrial membranes requires tBid (caspase-8-cleaved Bid) and a mitochondrial protein. Biochem. J. 368: 915–921.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. Jensen RE (2005) Control of mitochondrial shape. Curr. Opin. Cell. Biol. 17: 384–388.

    CAS  PubMed  Article  Google Scholar 

  75. Youle RJ and Karbowski M (2005) Mitochondrial fission in apoptosis. Nat. Rev. Mol. Cell. Biol. 6: 657–663.

    CAS  PubMed  Article  Google Scholar 

  76. Scorrano L (2005) Proteins that fuse and fragment mitochondria in apoptosis: con-fissing a deadly con-fusion? J. Bioenerg. Biomembr. 37: 165–170.

    CAS  PubMed  Article  Google Scholar 

  77. Roesch K, Curran SP, Tranebjaerg L and Koehler CM (2002) Human deafness dystonia syndrome is caused by a defect in assembly of the DDP1/TIMM8a-TIMM13 complex. Hum. Mol. Genet. 11: 477–486.

    CAS  PubMed  Article  Google Scholar 

  78. Koehler CM (2004) New developments in mitochondrial assembly. Annu. Rev. Cell. Dev. Biol. 20: 309–335.

    CAS  PubMed  Article  Google Scholar 

  79. Hille B (2001) Ionic Channels of Excitable Membranes. (Sunderland, MA: Sinauer Assoc.) pp. 351–352.

    Google Scholar 

Download references


This research was supported by NIH Grant GM57249 and NSF Grants MCB-0235834 and INT003797 to KWK. We thank Stephen Manon (Bordeaux, France) for his insightful and lively discussions and Cynthia Hughes for her excellent technical assistance. Finally, we gratefully acknowledge the huge contribution of Stan Korsmeyer to our own research program through his many years of active support and intellectual stimulation.

Author information

Authors and Affiliations


Corresponding author

Correspondence to K W Kinnally.

Additional information

Edited by C Borner

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Dejean, L., Martinez-Caballero, S. & Kinnally, K. Is MAC the knife that cuts cytochrome c from mitochondria during apoptosis?. Cell Death Differ 13, 1387–1395 (2006).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


  • MAC
  • mitochondrial apoptosis-induced channel
  • apoptosis
  • cytochrome c
  • patch-clamp
  • Bcl-2
  • Bax
  • t-Bid

Further reading


Quick links