Outer mitochondrial membrane permeability

Iaccarino, I., Hancock, D., Evan, G., and Downward, J. (2003) c-Myc induces cytochrome c release in Rati fibroblasts by increasing outer mitochondrial membrane permeability in a Bid-dependent manner. Cell Death Differ. 10, 599-608. 

FIGURE 31-7 Mitochondrial carriers. Ions and small molecules enter the intermembrane space, since the outer mitochondrial membrane is not a significant permeability barrier. However, the inner mitochondrial membrane is impermeable to ions except those for which there are specific carriers. Most of the carriers are reversible, as indicated by two-headed arrows. Compounds transported in one direction are indicated in red. The ATP/ADP translocase and the aspartate-glutamate carrier are both electrophoretic their transport is driven in the direction of the mitochondrial membrane potential, as indicated by red arrows. Glutamine is carried into the matrix by an electroneutral carrier. The unimpaired functioning of mitochondrial carriers is essential for normal metabolism. (Adapted with permission from reference [70].)... 

During apoptosis, the mitochondrial permeability is altered and apoptosis-specific protease activators are released from this organelle. The discontinuity of the outer mitochondrial membrane results in the release of cytochrome C to the cytosol followed by subsequent depolarization of the inner mitochondrial membrane (C5, PI). The release of cytochrome C further promotes activation of cas-pases, which are important molecules for initiating apoptosis (T6). Apoptosis inducing factor (AIF), another molecule released into the cytoplasm, has proteolytic activity and is by itself sufficient to induce apoptosis. 

Crouser, E.D., Julian, M. W., Blaho, D. V., and Pfeiffer, D. R., 2002a, Endotoxin-induced mitochondrial damage correlates with impaired respiratory activity, Crit. Care Med. 30, pp. 276-284 Crouser, E.D., Julian, M. W., Huff, J. E., Joshi, M. S., Bauer, J. A., Gadd, M. E., Wewers, M. D., and Pfeiffer, D. R., 2004, Abnormal permeability of inner and outer mitochondrial membranes contributes independently to mitochondrial dysfunction in the liver during acute endotoxemia, Crit Care Med. 32, pp. 478-488... 

Figure 17.3. Permeability transition pore (PTP). The PTP consists of voltage-dependent anion channel (VDAC), adenine nucleotide translocase (ANT) and several associated molecules including cyclophilin D (CypD) and peripheral benzodiazepine receptor (PBR). IMM, inner mitochondrial membrane OMM, outer mitochondrial membrane CytC, cytochrome c.

Figure 17.7. Two types of mitochondrial membrane permeabilization. Upper Bax/Bak pore leads to release of intermembrane space proteins, but the inner membrane is intact. Lower PTP (permeability transition pore) opening destroys the impermeability of the inner mitochondrial membrane (IMM). The pore opening causes influx of solutes and water into the matrix resulting in swelling. The mitochondrial swelling ruptures outer mitochondrial membrane (OMM). CypD, cyclophilin D.

A steady flow of metabolites both in and out of the mitochondrial matrix space is necessary for mitochondria to perform functions which involve the participation of enzymes inside the membrane permeability barrier. These functions include oxidative phosphorylation and therefore O2, ADP, phosphate and electron-rich substrates such as pyruvate, fatty acids and ketone bodies must enter the mitochondria, and the products, HjO, CO2 and ATP must leave. Although Oj, HjO and CO2 are permeable to the inner mitochondrial membrane [1,2], most metabolites are not, because of their highly hydrophiUc nature. The outer mitochondrial membrane does not present a significant barrier to hydrophilic metabolites because of the presence of large unregulated channels composed of the membrane protein, porin [3]. The inner mitochondrial membrane has a much larger surface area [4] than the outer membrane and a much higher ratio of protein to lipid [5]. It is composed not only of proteins involved in electron transport and oxidative phosphorylation but also specialized proteins which facilitate, and in many cases provide, directionality to the transport of metabolites [6]. 

The Bcl-2 family of proteins are considered as apoptosis regulating proteins. Members of this family are the Bcl-2 and Bcl-xL which are anti-apoptotic while Bax, Bad, Bid, Bim are pro-apoptotic. Fro-apoptotic and anti-apoptotic Bcl-2 proteins can bind directly to the components of mitochondrial pore, leading to either its opening or closure respectively.16 Figure 1. Alternatively, pro-apoptotic members, such as Bak or Bax, insert into the outer mitochondrial membrane where they oligomerize to form a permeable pore.17 Furthermore, an interaction between the intrinsic and the extrinsic... 

The outer mitochondrial membrane is freely permeable to substances of molecular weight less than 10,000 g/mol. The inner mitochondrial membrane is highly impermeable. 

The discovery in 1948 by Eugene Kennedy and Albert Lehninger that mitochondria are the site of oxidative phosphorylation in eukaryotes marked the beginning of the modern phase of studies in biological energy transductions. Mitochondria, like gramnegative bacteria, have two membranes (Fig. 19-1). The outer mitochondrial membrane is readily permeable to small molecules <5,000) and... 

Fig. 3. Oxidative metabolism in mitochondria. The inner mitochondrial membrane forms infoldings, called cristae, which enclose the mitochondrial matrix. Most of the enzymes for the TCA cycle, the P-oxidation of fatty acids, and for mitochondrial DNA synthesis are found in the matrix. ATP synthase and the protein complexes of the electron transport chain are embedded in the inner mitochondrial membrane. The outer mitochondrial membrane is permeable to small ions, but the inner mitochondrial membrane is impermeable.

Mitochondria and cell death Although oxidative phosphorylation is a mitochondrial process, most ATP utilization occurs outside of the mitochondrion. ATP synthesized from oxidative phosphorylation is actively transported from the matrix to the intermembrane space by adenine nucleotide translocase (ANT). Porins form voltage-dependent anion channels (VDAC) through the outer mitochondrial membrane for the diffusion of H2O, ATP metabolites, and other ions. Under certain types of stress, ANT, VDAC, and other proteins form a nonspecific open channel known as the mitochondrial permeability transition pore. This pore is associated with events that lead rapidly to necrotic cell death. 

Whereas the inner mitochondrial membrane is highly impermeable, the outer mitochondrial membrane is permeable to compounds with a molecular weight up to approximately 6,000 daltons because it contains large nonspecific pores called volt-age-dependent anion channels (VDAC) that are formed by mitochondrial porins (see Fig. 21.13). Unlike most transport proteins, which are membrane-spanning helices with specific binding sites, VDACs are composed of porin homodimers that form a p-barrel with a relatively large nonspecific water-filled pore through the center. These channels are open at low transmembrane potential, with a preference for anions such as phosphate, chloride, pyruvate, citrate, and adenine nucleotides. 

A key event in preventing apoptosis is thus the retention of cytochrome c within mitochondria. The permeability transition pore complex is formed between the inner and outer mitochondrial membranes and is reported to control protein release from the intermembrane space. The permeabihty transition pore complex comprises the adenine nucleotide transporter, the voltage-dependent anion channel and possibly other proteins such as the benzodiazepine receptor and cyclophilin D [65]. Thus, cells possess specialised systems and processes for retaining cytochrome c within mitochondria to ensure survival, as well as systems that can rapidly mobilise this molecule when the apoptotic pathway is triggered. 

Bax, Bak or BH3-only proteins can enhance the permeability of the mitochondrial outer mitochondrial membrane and these proteins might promote mitochondrial fission and finally unleash apoptogenic proteins including AIF. Since either Bak or Bax need to couple to BH3-only proteins for the release of pro-apoptotic proteins, BH3-only proteins act upstream of Bax- and... 

Figure 3. Schematic architecture of mitochondrial protein complexes. A transmembrane channel, called the permeability transition pore (FTP), is formed at the contaa sites between the inner and outer mitochondrial membrane (OM) of the mitochondria. The core components of PTP are the voltage-dependent anion channel (VDAC) in the outer membrane and the adenine nucleotide translocator (ANT) in the inner membrane (IM). VDAC allows diilusion of small molecules (<5 kDa), however ANT is only permeable to a few selected ions and metabolites and is responsible for maintaining the proton concentration gradient (pH) and the membrane elearic potential (A P,J. PTP is sometimes connected to destruction of permeability barrier and loss of the inner membrane potential and eventually results in mitochondrial membrane permeability transition during apoptosis and other specialized forms of cell death. Bax, Bak, Bc1-Xl and Bcl-2 locate in the outer membrane and may regulate the outer membrane permeability. The translocase of the outer membrane (TOM) and the translocase of the inner membrane (TlM) mediate protein import pathway in the mitochondria. Cy-D, cyclophilin D PBR, peripheral benzodiazepine receptor HK, hexokinase mtHSP70, mitochondrial heat shock protein 70.

A Upid membrane provides no barrier for O2 diffusion, its permeability coefficient being 40 cm which is 20% higher than the O2 permeabihty coefficient of an H2O layer of the same thickness. Inside cells, most of O2 flux occurs not by passive diffusion of O2, which is insufficiently soluble in H2O to provide required fluxes, but by diffusion of oxymyoglobin, which unloads O2 at the point of O2 consumption (e.g., at the outer mitochondrial membrane). 

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