Protein import, into mitochondria

This zinc-dependent enzyme [EC 3.4.24.59] of the peptidase M3 family catalyzes the hydrolysis of a peptide bond such that there is a release of an N-terminal octa-peptide at the second stage of processing of some proteins imported into the mitochondrion. The natural substrates are precursor proteins that already have been processed by the mitochondrial processing peptidase. 

After synthesis In the cytosol, the soluble precursors of mitochondrial proteins (Including hydrophobic Integral membrane proteins) interact directly with the mitochondrial membrane. In general, only unfolded proteins can be imported Into the mitochondrion. Chaperone proteins such as cytosolic Hsc70 keep nascent and newly made proteins in an unfolded state, so that they can be taken up by mitochondria. Import of an unfolded mitochondrial precursor is initiated by the binding of a mitochondrial targeting sequence to an import receptor in the outer mitochondrial membrane. These receptors were first identified by experiments in which antibodies to specific proteins of the outer mitochondrial membrane were shown to inhibit protein import into... 

A variety of protein import pathways into the vacuole are known (Burd et al., 1998 Bryant and Stevens, 1998). It includes the sorting from the Golgi apparatus, endocytosis, autophagy (where a part of the cytoplasm such as a mitochondrion is engulfed into a newly formed vacuole and is degraded), direct import from the cytosol, and the vacuolar inheritance from the mother cell. Of these, the pathways from the Golgi... 

Figure 12.37. A Mitochondrial Targeting Sequence. This sequence is recognized by receptors on the external face of the outer mitochondrial membrane. A protein bearing the sequence will be imported into the mitochondrion. Hydrophobic residues are shown in yellow, basic ones in blue, and serine and threonine in red.

All three respiratory complexes are typical integral membrane proteins that span the inner mitochondrial membrane. Each consists of several different subunits, the exact number of which is still under debate. The genes of some subunits of cytochrome oxidase and the />c, complex are in mitochondrial DNA (mtDNA). These proteins are synthesised inside the mitochondrion. However, most proteins of these complexes, as well as cytochrome c, are synthesised on cytoplasmic ribosomes and coded by the nuclear genome. This raises intriguing questions of how the latter are imported into the mitochondrion and inserted into the mitochondrial membrane, as well as of how mitochondrial and cytoplasmic transcription and translation are synchronised [3-5]. 

Figure 16-26 presents an overview of protein import from the cytosol into the mitochondrial matrix, the route into the mitochondrion followed by most imported proteins. We will discuss in detail each step in protein transport into the matrix... 

Mitochondrial DNA is small and codes for relatively few mitochondrial proteins. Although mitochondria contain their own protein synthesis machinery, the majority of the hundreds of mitochondrial proteins are coded for by nuclear genes. These proteins are synthesized in the cytoplasm and imported into the mitochondria. Plastid DNA is somewhat larger than that of the mitochondrion and contains the genetic information for more chloroplast proteins. However, as is the case for mitochondria, most of the proteins in a chloroplast are coded by nuclear genes... 

Some insights into these questions may be gained by considering current knowledge about the biosynthesis of the ATPase and cytochrome oxidase complexes of mitochondria. Each of these two enzymes is composed of multiple subunits belonging to both the intrinsic and extrinsic classes of proteins. It has been shown that the extrinsic components (Fi and OSCP) are synthesized on cytoplasmic ribosomes and are imported into the mitochondrion, while the intrinsic subunits are synthesized in the mitochondrion. The respiratory complex, cytochrome oxidase, has also been found to be dually derived from cytoplasmic and mitochondrial protein synthesis (refs. 15, 16, Chapter 5). This enzyme consists of seven nonidentical polypeptides, three of which are made in mitochondria and four in cytoplasmic ribosomes. The cytoplasmic products are extrinsic proteins by the aforementioned criteria, whereas the mitochondrial products are markedly hydrophobic. 

Protein trafficking has been extensively studied in fungi and mammals, and a number of elaborate machines have been described that specifically import certain proteins into typical eukaryotic organelles such as the nucleus, the endoplasmic reticulum and the mitochondrion. 

A FIGURE 18-1 Overview of synthesis of major membrane lipids and their movement into and out of cells. Membrane lipids (e.g., phospholipids, cholesterol) are synthesized through complex multienzyme pathways that begin with sets of water-soluble enzymes and intermediates in the cytosol (D) that are then converted by membrane-associated enzymes into water-insoluble products embedded in the membrane (B), usually at the interface between the cytosolic leaflet of the endoplasmic reticulum (ER) and the cytosol. Membrane lipids can move from the ER to other organelles (H), such as the Golgi apparatus or the mitochondrion, by either vesicle-mediated or other poorly defined mechanisms. Lipids can move into or out of cells by plasma-membrane transport proteins or by lipoproteins. Transport proteins similar to those described in Chapter 7 that move lipids (0) include sodium-coupled symporters that mediate import CD36 and SR-BI superfamily proteins that can mediate... 

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