Inner mitochondrial membrane impermeability

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. 

Most of the NADH used in electron transport is produced in the mitochondrial matrix space, an appropriate site because NADH is oxidized by Complex I on the matrix side of the inner membrane. Furthermore, the inner mitochondrial membrane is impermeable to NADH. Recall, however, that NADH is produced in glycolysis by glyceraldehyde-3-P dehydrogenase in the cytosol. If this NADH were not oxidized to regenerate NAD, the glycolytic pathway would cease to function due to NAD limitation. Eukaryotic cells have a number of shuttle systems that harvest the electrons of cytosolic NADH for delivery to mitochondria without actually transporting NADH across the inner membrane (Figures 21.33 and 21.34). 

THE RELATIVE IMPERMEABILITY OF THE INNER MITOCHONDRIAL MEMBRANE NECESSITATES EXCHANGE TRANSPORTERS... 

Because the inner mitochondrial membrane is impermeable to protons and other ions, special exchange transporters span the membrane to allow passage of ions such as OH, Pf, ATP , ADP, and metabo-htes, without discharging the electrochemical gradient across the membrane. 

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].)... 

Both mitochondrial membranes are very rich in proteins. Porins (see p. 214) in the outer membrane allow small molecules (< 10 kDa) to be exchanged between the cytoplasm and the intermembrane space. By contrast, the inner mitochondrial membrane is completely impermeable even to small molecules (with the exception of O2, CO2, and H2O). Numerous transporters in the inner membrane ensure the import and export of important metabolites (see p. 212). The inner membrane also transports respiratory chain complexes, ATP synthase, and other enzymes. The matrix is also rich in enzymes (see B). 

Although the primary role of the proton gradient in mitochondria is to furnish energy for the synthesis of ATP, the proton-motive force also drives several transport processes essential to oxidative phosphorylation. The inner mitochondrial membrane is generally impermeable to charged species, but two specific systems transport ADP and Pj into the matrix and ATP out to the cytosol (Fig. 19-26). 

The inner mitochondrial membrane is impermeable to NADH and NAD+, but NADH equivalents are moved from the cytosol to the matrix by either of two shuttles. NADH equivalents moved in by the malate-aspartate shuttle enter the respiratory chain at Complex I and yield a P/O ratio of 2.5 those moved in by the glycerol 3-phosphate shuttle enter at CoQ and give a P/O ratio of 1.5. 

The inner mitochondrial membrane is impermeable to most charged or hydrophilic substances. However, it contains numerous transport proteins that permit passage of specific molecules from the cytosol (or more correctly, the intermembrane space) to the mitochondrial matrix. 

Oxaloacetate, the product of the first step in gluconeogenesis, must leave the mitochondrion and enter the cytosol where the subsequent enzyme steps take place. Since the inner mitochondrial membrane is impermeable to oxaloacetate, it is converted to malate by mitochondrial malate dehydrogenase. This leaves the mitochondrion and is converted back to oxaloacetate in the cytosol by cytoplasmic malate dehydrogenase. 

Reoxidation of The inner mitochondrial membrane is impermeable to NADH. Therefore NADH... 

While short-chain fatty acids can move across the mitochondrial membrane directly and are then activated in the mitochondrial matrix, the inner mitochondrial membrane is impermeable to longer fatty acids, such as palmitate. A small molecule, carnitine, serves as a... 

Mitochondria perform a crucial series of reactions in the human organism. The inner mitochondrial membrane is relatively impermeable to charged substances, although uncharged substances, such as Oz and CO, move across with ease. To perform their functions, however, mitochondria must transport various charged substances in and out of its matrix. This is done via transport particles called porters or translocases (see Chapter 9 for definitions). They are not directly associated with the hydrolysis of ATP some depend for their operation on concentration gradients of one sort or another, and others depend on the mitochondrial membrane potential. 

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.

Inside the inner membrane of a mitochondrion is a viscous region known as the matrix (Fig. 1-9). Enzymes of the tricarboxylic acid (TCA) cycle (also known as the citric acid cycle and the Krebs cycle), as well as others, are located there. For substrates to be catabolized by the TCA cycle, they must cross two membranes to pass from the cytosol to the inside of a mitochondrion. Often the slowest or rate-limiting step in the oxidation of such substrates is their entry into the mitochondrial matrix. Because the inner mitochondrial membrane is highly impermeable to most molecules, transport across the membrane using a carrier or transporter (Chapter 3, Section 3.4A) is generally invoked to explain how various substances get into the matrix. These carriers, situated in the inner membrane, might shuttle important substrates from the lumen between the outer and the inner mitochondrial membranes to the matrix. Because of the inner membrane, important ions and substrates in the mitochondrial matrix do not leak out. Such permeability barriers between various subcellular compartments improve the overall efficiency of a cell. 

VDAC plays a role in the regulated flux of metabolites—usually anionic species such as phosphate, chloride, organic anions, and the adenine nucleotides—across the outer membrane. VDAC appears to form an open p -barrel structure similar to that of the bacterial porins (Section 12.5.2). although mitochondrial porins and bacterial porins may have evolved independently. Some cytoplasmic kinases bind to VDAC, thereby obtaining preferential access to the exported ATP. In contrast, the inner membrane is intrinsically impermeable to nearly all ions and polar molecules. A large family of transporters shuttles metabolites such as ATP, pyruvate, and citrate across the inner mitochondrial membrane. The two faces of this membrane will be referred to as the matrix side and the cytosolic side (the latter because it is freely accessible to most small molecules in the cytosol). They are also called the N and P sides, respectively, because the membrane potential is negative on the matrix side and positive on the cytosolic side. 

The inner mitochondrial membrane must he impermeable to most molecules, yet much exchange has to take place between the cytosol and the mitochondria. This exchange is mediated by an array of membrane-spaiming transporter proteins (Section 13,4). 

Oxaloacetate formed in the transfer of acetyl groups to the cytosol must now be returned to the mitochondria The inner mitochondrial membrane is impermeable to oxaloacetate. Hence, a series of bypass reactions are needed. Most important, these reactions generate much of the NADPH needed for fatty acid synthesis. First, oxaloacetate is reduced to malate by NADH. This reaction is catalyzed by a malate dehydrogenase in the cytosol. 

Long chain fatty acids are are bound to Fatty acid binding protein for transport within the cytosol. They are impermeable to the inner mitochondrial membrane. They are thus esterified in the cytosol by microsomal Fatty acyl CoA synthetase in a reaction identical to the one shown above. Again the reaction is driven by the hydrolysis of pyrophosphate. The enzyme involves an acyl AMP intermediate ... 

The inner mitochondrial membrane is impermeable to protons. The protons can reenter the matrix only through the ATP synthase complex (the F0-F1/ATPase), causing ATP to be generated. 

PEP carboxykinase is found within the mitochondria of some species and in the cytoplasm of others. In humans this enzymatic activity is found in both compartments. Because the inner mitochondrial membrane is impermeable to OAA, cells that lack mitochondrial PEP carboxykinase transfer OAA into the cytoplasm by using, for example, the malate shuttle. In this process, OAA is converted into malate by mitochondrial malate dehydrogenase. After the transport of malate across mitochondrial membrane, the reverse reaction is catalyzed by cytoplasmic malate dehydrogenase. 

A summary of the sources of ATP produced from one molecule of glucose is provided in Table 10.2. ATP production from fatty acids, the other important energy source, is discussed in Chapter 12. Several aspects of this summary require further discussion. Recall that two molecules of NADH are produced during glycolysis. When oxygen is available, the oxidation of this NADH by the ETC is preferable (in terms of energy production) to lactate formation. The inner mitochondrial membrane, however, is impermeable to NADH. Animal cells have evolved several shuttle mechanisms to transfer electrons from cytoplasmic NADH to the mitochrondrial ETC. The most prominent examples are the glycerol phosphate shuttle and the malate-aspartate shuttle. 

A FIGURE 8-10 The malate shuttle. This cyclical series of reactions transfers electrons from NADH in the cytosol (intermembrane space) across the inner mitochondrial membrane, which is impermeable to NADH itself. StepH Cytosolic malate dehydrogenase transfers electrons from cytosolic NADH to oxaloacetate, forming malate. StepH An antiporter (blue oval) in the inner mitochondrial membrane transports malate into the matrix in exchange for a-ketoglutarate. StepH Mitochondrial malate dehydrogenase converts malate back to oxaloacetate, reducing NAD in the matrix to NADH in the process. StepH Oxaloacetate, which cannot directly cross the inner membrane, is converted to... 

The inner membrane is highly folded to create a large surface area. The folded membranes are known as cristae. The inner mitochondrial membrane is almost completely impermeable to most substances. For this reason it has many transport proteins to bring particular fuel molecules into the matrix space. Also embedded within the inner mitochondrial membrane are the protein electron carriers of the electron transport system and ATP synthase. ATP synthase is a large complex of many proteins that catalyzes the s)mthesis of ATP. 

The mitochondria are aerobic cell organelles that are responsible for most of the ATP production in eukaryotic cells. They are enclosed by a double membrane. The outer membrane permits low-molecular-weight molecules to pass through. The inner mitochondrial membrane, by contrast, is almost completely impermeable to most molecules. The inner mitochondrial membrane is the site where oxidative phosphorylation occurs. The enzymes of the citric acid cycle, of amino acid catabolism, and of fatty acid oxidation are located in the matrix space of the mitochondrion. 

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. 

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