Translocase-of-the-inner membrane

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.

Whereas the mitochondrial enzymes of p-oxidation reside within the area bound by inner membrane, activation of fatty acids proceeds largely at sites exterior to this membrane. The transport of activated acyl groups across the inner mitochondrial membrane Is brought about by a carnitine dependent route (Fritz, 1963 Bremer, 1968 Bressler, 1970). A carnitine acyltransferase localized on the outer aspect of inner membrane utilizes cytosolic free carnitine to convert the cytosolic acyl-CoA to cytosolic acylcarnitine (Fig. 1). A translocase of the inner membrane then moves the acylcarnitine inside in exchange for the simultaneous movement of carnitine in the opposite direction. Another carnitine acyltransferase, situated on the inner side of the inner membrane, utilizes matrix CoA to convert acylcarnitine to acyl-CoA, thus producing the latter in the same compartment where enzymes of the p-oxidation spiral exist (Pande, 1975 Ramsay and Tubbs, 1975 Tubbs and... 

Figure 7.11 Mechanism of transport of long-chain fatty adds across the inner mitochondrial membrane as fatty acyl carnitine. CRT is the abbreviation for carnitine palmitoyl transferase. CPT-I resides on the outer surface of the inner membrane, whereas CPT-II resides on the inner side of the inner membrane of the mitochondria. Transport across the inner membrane is achieved by a carrier protein known as a translocase. FACN - fatty acyl carnitine, CN - carnitine. Despite the name, CRT reacts with long-chain fatty acids other than palmitate. CN is transported out of the mitochondria by the same translocase.

Fig-i Mitochondrial protein import machinery as defined in S. cerevisiae. TOM translo-case of the outer mitochondrial membrane SAM sorting and assembly machinery TIM translocase of the inner mitochondrial membrane MIA mitochondrial IMS import and assembly machine PAM presequence translocase associated motor IMP inner membrane protease MPP mitochondrial processing peptidase. The numbers on the individual Tom, Sam, Tim or Pam components represent their approximate molecular masses in kDa. See text for mechanistic details. Adopted from Dolezal et al. 2006... 

A second membrane transport system essential to oxidative phosphorylation is the phosphate translocase, which promotes symport of one H2PO4 and one H+ into the matrix. This transport process, too, is favored by the transmembrane proton gradient (Fig. 19-26). Notice that the process requires movement of one proton from the P to the N side of the inner membrane, consuming some of the energy of electron transfer. A complex of the ATP synthase and both translocases, the ATP synthasome, can be isolated from... 

The inner membrane is studded with spheres, each 8-10 nm in diameter, that are attached via stalks 4-5 nm in length. These inner membrane spheres are present on the matrix side (M-side) but absent from the cytoplasmic side (C-side). The components of the inner membrane include respiratory chain proteins, a variety of transport molecules, and a part of the ATP-synthesizing apparatus (the base piece of ATP synthase). The ATP-ADP translocase and... 

In muscle, most of the fatty acids undergoing beta oxidation are completely oxidized to C02 and water. In liver, however, there is another major fate for fatty acids this is the formation of ketone bodies, namely acetoacetate and b-hydroxybutyrate. The fatty acids must be transported into the mitochondrion for normal beta oxidation. This may be a limiting factor for beta oxidation in many tissues and ketone-body formation in the liver. The extramitochondrial fatty-acyl portion of fatty-acyl CoA can be transferred across the outer mitochondrial membrane to carnitine by carnitine palmitoyltransferase I (CPTI). This enzyme is located on the inner side of the outer mitochondrial membrane. The acylcarnitine is now located in mitochondrial intermembrane space. The fatty-acid portion of acylcarnitine is then transported across the inner mitochondrial membrane to coenzyme A to form fatty-acyl CoA in the mitochondrial matrix. This translocation is catalyzed by carnitine palmitoyltransferase II (CPTII Fig. 14.1), located on the inner side of the inner membrane. This later translocation is also facilitated by camitine-acylcamitine translocase, located in the inner mitochondrial membrane. The CPTI is inhibited by malonyl CoA, an intermediate of fatty-acid synthesis (see Chapter 15). This inhibition occurs in all tissues that oxidize fatty acids. The level of malonyl CoA varies among tissues and with various nutritional and hormonal conditions. The sensitivity of CPTI to malonyl CoA also varies among tissues and with nutritional and hormonal conditions, even within a given tissue. Thus, fatty-acid oxidation may be controlled by the activity and relative inhibition of CPTI. 

Fig. 20.20. Model for the import of nuclear-encoded proteins into the mitochondrial matrix. The matrix preprotein with its positively charged N-terminal presequence is shown in blue. Abbreviations OM, outer mitochondrial membrane IMS, intramembrane space IM, inner mitochondrial membrane TOM, translocases of the outer mitochondrial membrane TIM, translocases of the inner mitochondrial membrane mthspTO, mitochondrial heat shock protein 70.

Acyl CoA is formed in the cytosol, and the enzymes of the (3-oxidation pathway are in the matrix of the mitochondrion. The mitochondrial inner membrane is impermeable to CoA and its acyl derivatives. However, a translocase protein can shuttle carnitine and its acyl derivatives across the inner mitochondrial membrane. The acyl group is transferred to carnitine on the cytosol side of the inner membrane and back to CoA on the matrix side. Thus, carnitine acts as a transmembrane carrier of acyl groups. 

Carnitine (p-hydroxy-y-trimethylammonium butyrate), (CHjljN"—CH2—CH(OH)—CH2—COO , is widely distributed and is particularly abundant in muscle. Long-chain acyl-CoA (or FFA) will not penetrate the inner membrane of mitochondria. However, carnitine palmitoyltransferase-I, present in the outer mitochondrial membrane, converts long-chain acyl-CoA to acylcarnitine, which is able to penetrate the inner membrane and gain access to the P-oxidation system of enzymes (Figure 22-1). Carnitine-acylcar-nitine translocase acts as an inner membrane exchange transporter. Acylcarnitine is transported in, coupled with the transport out of one molecule of carnitine. The acylcarnitine then reacts with CoA, cat-... 

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].)... 

A few patients have been described with a defect involving the carnitine-acylcarnitine translocase system, which facilitates the movement of long-chain acylcarnitine esters across the inner membrane of the mitochondrion (Fig. 42-2). These patients have extremely low carnitine concentrations and minimal dicarboxylic aciduria [4]. 

There are several hypotheses for a specific mechanism by which ONOO- can control the open state of the PTPC. Briefly the PTPC is regulated by primary constituents of the pore, including the inner membrane adenine nucleotide translocase (ANT) and the outer membrane protein voltage-dependent anion channel (VDAC or porin). The VDAC-ANT complex can bind to signaling proteins that modulate permeability transition, such as pro-apoptotic Bax (which opens the pore) and anti-apoptotic Bcl-2... 

Rassow J, Dekker PJ, van Wilpe S, Meijer M, Soli J (1999) The preprotein translocase of the mitochondrial inner membrane function and evolution. J Mol Biol 286 105-120... 

The adenine nucleotide translocase, integral to the inner membrane, binds ADP3 - in the intermembrane space and transports it into the matrix in exchange for an ATP4 molecule simultaneously transported outward (see Fig. 13-1 for the ionic forms of ATP and ADP). Because this antiporter moves four negative charges out for every three moved in, its activity is favored by the... 

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