Outer mitochondrial membrane composition

The most important membranes in animal cells are the plasma membrane, the inner and outer nuclear membranes, the membranes of the endoplasmic reticulum (ER) and the Golgi apparatus, and the inner and outer mitochondrial membranes. Lysosomes, peroxisomes, and various vesicles are also separated from the cytoplasm by membranes. In plants, additional membranes are seen in the plastids and vacuoles. All membranes show polarity—e., there is a difference in the composition of the inner layer (facing toward the cytoplasm) and the outer layer (facing away from it). 

By definition, the uncoupling effect of certain flavonoids should be independent of their inhibitory effects on mitochondrial respiration or FoFi-ATPase, suggesting an additional mode of action of flavonoids against mitochondrial function. A collapse of the transmembrane potential is likely under conditions in which the permeability barrier created by the mitochondrial inner membrane is compromised (as occurs in the presence of ionophores). Calcium, phosphate, oxidative stress, adenine nucleotide depletion, and membrane depolarization can induce such a nonspecific increase in the permeability of the inner membrane, in an event called the mitochondrial permeability transition (MPT) [30,34]. The MPT can be selectively inhibited by cyclosporin A and is believed to involve the assembly of a multiprotein complex to form a nonspecific pore that spans the inner and outer mitochondrial membranes. The latter assembly is referred to as the permeability transition pore complex (PTPC) (Fig. 1). Its exact composition is unknown, but appears to comprise cyclophilin D, ANT, the voltage-dependent anion channel (porin), and a benzodiazepinebinding site [10,30,34]. 

The mitochondrial permeability transition (MPT) is the loss of the inner mitochondrial membrane impermeability to solutes caused by opening of the MPT pore (MPTP). In turn, this action results in a loss of mitochondrial function and provides a common mechanism implicated in activation of mi-tophagy/autophagy, apoptosis, and necrosis in different cell systems. Although the composition of MPTP is not fully settled, multiple studies suggest involvement of adenine nucleotide translocase (ANT) in the inner mitochondrial membrane, voltage-dependent anion channel (VDAC or porin) in the outer membrane, and cyclophilin D (CypD) in the matrix. 

In the plasma membrane of animals (1), the amount of cholesterol is usually around 20-30 mol%. The rest of the lipids are mainly PC, PE, and sphingomyelin (SM) lipids, with smaller amounts of PS, PI, and glycolipids. These lipids are distributed asymmetrically across the membrane, because most cholesterol, PC, and glycolipids are located in the extracellular (outer) leaflet, whereas PS and PE lipids are located mainly in the intracellular (inner) monolayer. The lipid composition can be highly different in other organelles, however, as is the case in mitochondria (1), in which the mitochondrial membrane is composed of two (inner and outer) membranes. There, the amounts of cholesterol, SM, and PS are negligible most lipids are PC and PE. The major difference compared with plasma membrane is the concentration of cardiolipins. They are actually found only in bacterial and in mitochondrial membranes, where their numbers are significant even in mitochondria they are located mainly on the iimer membrane. 

The essential role of cytochrome c release from injured mitochondria in the activation of caspase 9 has been alluded to above. This pathway is especially important in proapoptotic stimuli that are not initiated by surface receptors for apoptosis, such as UV irradiation, and may involve mitochondrial dependent pathways [83]. Continued respiration in the presence of an open mitochondrial pore may result in the generation of reactive oxygen species. Release of cytochrome c may be mediated by the opening of the mitochondrial FT pore, a non-selective channel whose composition is only partially defined [84]. Inhibitors of FT pore opening, such as cyclosporine, which binds to the adenine nucleotide translocator (ANT), a component of the FT pore, and bongkrekic acid, as well as Bcl-2, prevent cytochrome c release and inhibit apoptosis [85] whereas activators of the FT pore, such as atractyloside and Bax induce it [86]. Oxidants can rupture the outer membrane of mitochondria and release caspase-activating proteins [87]. Some studies have shown cytochrome c release before collapse of the mitochondrial membrane potential [83] suggesting alternate control of the FT pore. Many, but not all, of the members of the Bd-2 family of proteins reside in the inner mitochondrial membrane, form ionic channels in hpid membranes and increase rates of proton extrusion in mitochondria [88] and thus may control the FT pore. The antiapoptotic and mitochondrial affects of Bd-2 are independent of caspase activity as they occur in the presence of caspase inhibitors and also in yeast that lack caspases [86]. 

Although a great deal is known about the chemical composition of the mitochondrial membrane and it is established that the membrane contains a number of catalytic proteins e.g., the ATPase synthetase system, an ion transport molecular machinery and electron transport chain), the topological distribution of these proteins in the membrane is not known. All topological models proposed are at present hypothetical [177]. However, it is accepted that the mitochondrial membrane, like most if not all biological membranes, is of the fluid mosaic model and is composed of a lipid bilayer traversed by proteins (see plasma membrane in Chapter 16). Electron microscopic studies of the freeze-edge fractured faces of the outer and the inner membrane [178] indicate that the proteins are asymmetrically distributed not only when the inner is compared to the outer membrane, but also when the inner and outer faces of each of the fractured membranes are compared (Table 1-3). 

Stoffel, W. Schiefer, H.G. (1968) Hoppe-Seylers Z. Physiol. Chem., M9, 1017-1026. Biosynthesis and composition of phosphatides in outer and inner mitochondrial membranes. 

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