Outer-membrane transporters pyruvate

The next steps of glucose catabolism are called the citric acid cycle. The pyruvic acid formed in glycolysis is transported into the mitochondria, which arc subcellular organelles with double (inner and outer) membranes. They are referred to as the powerhous-... 

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. 

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]. 

A FIGURE 8-7 Summary of the aerobic oxidation of pyruvate and fatty acids in mitochondria. The outer membrane is freely permeable to all metabolites, but specific transport proteins (colored ovals) in the inner membrane are required to import pyruvate (yellow), ADP (green), and P (purple) into the matrix and to export ATP (green). NADH generated in the cytosol is not transported directly to the matrix because the inner membrane is impermeable to NAD and NADH instead, a shuttle system (red) transports electrons from cytosolic NADH to NAD in the matrix. O2 diffuses into the matrix and CO2 diffuses out. Stage 1 Fatty acyl groups are transferred from fatty acyl CoA and transported across the inner membrane via a special carrier (blue oval) and then reattached to CoA on the matrix side. 

Most of the newly synthesized ATP that is released into the mitochondrial matrix must be transported out of the mitochondria, where it is used for energy-requiring processes such as active ion transport, muscle contraction, or biosynthetic reactions. Likewise, ADP, phosphate, pyruvate, and other metabolites must be transported into the matrix. This requires transport of compounds through both the inner and outer mitochondrial membranes. 

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. 

Fig. 13.1.1. Schematic overview of mitochondrial oxidative phosphorylation. A part of the mitochondrion is represented, showing the outer mitochondrial membrane (OMM), inner mitochondrial membrane (IMM) and crista (an invagination of the inner membrane). Substrates for oxidation enter the mitochondrion through specific carrier proteins, e.g., the pyruvate transporter, (PyrT). Reducing equivalents from fatty acyl CoA dehydrogenases, pyruvate dehydrogenase and the TCA cycle are delivered to the electron transport chain through NADH, succinate ubiquinol oxidoreductase (SQO), electron transfer flavoprotein (ETF) and its ubiquinol-...

The five biotin-dependent mammalian carboxylases are acetyl-CoA carboxylase isoforms I and II (also known as a-ACC (EC 6.4.1.2) and /3-ACC (EC 6.4.1.2)), pyruvate carboxylase (EC 6.4.1.1), methyl-crotonyl-CoA carboxylase (EC 6.4.1.4), and propio-nyl-CoA carboxylase (EC 6.4.1.3). ACC catalyzes the incorporation of bicarbonate into acetyl-CoA to form malonyl-CoA (Figure 2). There are two isoforms of ACC. Isoform I is located in the cytosol and produces malonyl-CoA, which is rate limiting in fatty acid synthesis (elongation). Isoform II is located on the outer mitochondrial membrane and controls fatty acid oxidation in mitochondria through the inhibitory effect of malonyl-CoA on fatty acid transport... 

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