Proteins mitochondrial

The space inside the inner mitochondrial membrane is called the matrix, and it contains most of the enzymes of the TCA cycle and fatty acid oxidation. (An important exception, succinate dehydrogenase of the TCA cycle, is located in the inner membrane itself.) In addition, mitochondria contain circular DNA molecules, along with ribosomes and the enzymes required to synthesize proteins coded within the mitochondrial genome. Although some of the mitochondrial proteins are made this way, most are encoded by nuclear DNA and synthesized by cytosolic ribosomes. 

BH3 domain) of the BH3-only proteins binds to other Bcl-2 family members thereby influencing their conformation. This interaction facilitates the release of cytochrome C and other mitochondrial proteins from the intermembrane space of mitochondria. Despite much effort the exact biochemical mechanism which governs this release is not yet fully understood. The release of cytochrome C facilitates the formation of the apoptosome, the second platform for apoptosis initiation besides the DISC. At the apoptosome which is also a multi-protein complex the initiator caspase-9 is activated. At this point the two pathways converge. 

Mitochondria have their own DNA (mtDNA) and genetic continuity. This DNA only encodes 13 peptide subunits synthesized in the matrix that are components of complexes I, III, IV, and V of the respiratory chain. Most mitochondrial proteins are synthesized on cytoplasmic ribosomes and imported by specific mechanisms to their specific locations in the mitochondrion (see below). 

Fujiki, M. Vemer, K. (1993). Coupling of cytosolic protein synthesis and mitochondrial protein import in yeast. J. Biol. Chem. 268, 1914-1920. 

Pfanner, N., Rossow, J., van der Klei, I.J., Neupert W. (1992). A dynamic model of the mitochondrial protein import machinery. Cell 68,999-1002. 

Venter, K. (1992). Early events in yeast mitochondrial protein targeting. Mol. Microbiol. 6,1723-1728. 

Mitochondria are unique organelles in that they contain their own DNA (mtDNA), which, in addition to ribosomal RN A (rRNA) and transfer RN A (tRNA)-coding sequences, also encodes 13 polypeptides which are components of complexes I, III, IV, and V (Anderson et al., 1981). This fact has important implications for both the genetics and the etiology of the respiratory chain disorders. Since mtDNA is maternally-inherited, a defect of a respiratory complex due to a mtDNA deletion would be expected to show a pattern of maternal transmission. However the situation is complicated by the fact that the majority of the polypeptide subunits of complexes I, III, IV, and V, and all subunits of complex II, are encoded by nuclear DNA. A defect in a nuclear-coded subunit of one of the respiratory complexes would be expected to show classic Mendelian inheritance. A further complication exists in that it is now established that some respiratory chain disorders result from defects of communication between nuclear and mitochondrial genomes (Zeviani et al., 1989). Since many mitochondrial proteins are synthesized in the cytosol and require a sophisticated system of posttranslational processing for transport and assembly, it is apparent that a diversity of genetic errors is to be expected. 

Figure 46-1. Diagrammatic representation of the two branches of protein sorting occurring by synthesis on (1) cytosolic and (2) membrane-bound polyribosomes. The mitochondrial proteins listed are encoded by nuclear genes. Some of the signals used in further sorting of these proteins are listed in Table 46-4. (ER, endoplasmic reticulum GA, Golgi apparatus.)...

The sorting of proteins belonging to the cytosohc branch referred to above is described next, starting with mitochondrial proteins. 

The above describes the major pathway of proteins destined for the mitochondrial matrix. However, certain proteins insert into the outer mitochoiidrial membrane facilitated by the TOM complex. Others stop in the intermembrane space, and some insert into the inner membrane. Yet others proceed into the matrix and then return to the inner membrane or intermembrane space. A number of proteins contain two signaling sequences—one to enter the mitochondrial matrix and the other to mediate subsequent relocation (eg, into the inner membrane). Certain mitochondrial proteins do not contain presequences (eg, cytochrome Cy which locates in the inter membrane space), and others contain internal presequences. Overall, proteins employ a variety of mechanisms and routes to attain their final destinations in mitochondria. 

Nucleic acids are not the only biomolecules susceptible to damage by carotenoid degradation products. Degradation products of (3-carotene have been shown to induce damage to mitochondrial proteins and lipids (Siems et al., 2002), to inhibit mitochondrial respiration in isolated rat liver mitochondria, and to induce uncoupling of oxidative phosphorylation (Siems et al., 2005). Moreover, it has been demonstrated that the degradation products of (3-carotene, which include various aldehydes, are more potent inhibitors of Na-K ATPase than 4-hydroxynonenal, an aldehydic product of lipid peroxidaton (Siems et al., 2000). 

Not all the cellular DNA is in the nucleus some is found in the mitochondria. In addition, mitochondria contain RNA as well as several enzymes used for protein synthesis. Interestingly, mitochond-rial RNA and DNA bear a closer resemblance to the nucleic acid of bacterial cells than they do to animal cells. For example, the rather small DNA molecule of the mitochondrion is circular and does not form nucleosomes. Its information is contained in approximately 16,500 nucleotides that func-tion in the synthesis of two ribosomal and 22 transfer RNAs (tRNAs). In addition, mitochondrial DNA codes for the synthesis of 13 proteins, all components of the respiratory chain and the oxidative phosphorylation system. Still, mitochondrial DNA does not contain sufficient information for the synthesis of all mitochondrial proteins most are coded by nuclear genes. Most mitochondrial proteins are synthesized in the cytosol from nuclear-derived messenger RNAs (mRNAs) and then transported into the mito-chondria, where they contribute to both the structural and the functional elements of this organelle. Because mitochondria are inherited cytoplasmically, an individual does not necessarily receive mitochondrial nucleic acid equally from each parent. In fact, mito-chondria are inherited maternally. 

Dewey, R.E., Timothy, D.H., and Levings III., C.S. (1987) A mitochondrial protein associated with cytoplasmic male sterility in the T cytoplasm of maize. Proc. Natl. Acad. Sci. USA 84, 5374-5378. 

Mitochondrial DNA is inherited maternally. What makes mitochondrial diseases particularly interesting from a genetic point of view is that the mitochondrion has its own DNA (mtDNA) and its own transcription and translation processes. The mtDNA encodes only 13 polypeptides nuclear DNA (nDNA) controls the synthesis of 90-95% of all mitochondrial proteins. All known mito-chondrially encoded polypeptides are located in the inner mitochondrial membrane as subunits of the respiratory chain complexes (Fig. 42-3), including seven subunits of complex I the apoprotein of cytochrome b the three larger subunits of cytochrome c oxidase, also termed complex IV and two subunits of ATPase, also termed complex V. 

Defects of nuclear DNA also cause mitochondrial diseases. As mentioned above, the vast majority of mitochondrial proteins are encoded by nDNA, synthesized in the cytoplasm and imported into the mitochondria through a complex series of steps. Diseases can be due to mutations in genes encoding respiratory chain subunits, ancillary proteins controlling the proper assembly of the respiratory chain complexes, proteins controlling the importation machinery, or proteins controlling the lipid composition of the inner membrane. All these disorders will be transmitted by mendelian inheritance. From a biochemical point of view, all areas of mitochondrial metabolism can be affected (see below). 

Most of the mitochondrial proteins are nuclear encoded and thus must be targeted into mitochondria and sorted into some of their components after their synthesis at the cytosol. Because mitochondria have two membranes, there are four localization sites the matrix, the inner membrane, the intermembrane space, and the outer membrane (Fig. 6). Although there has been considerable progress in our understanding of these processes, some questions still remain. Moreover, the total picture is rather complicated and contains many exceptions. A simplified view is presented here based mainly on the view of Pfanner and Mihara (Mihara and Omura, 1996 Pfanner et al., 1997 Pfanner, 1998). There are also a number of other excellent reviews on this subject (Schatz, 1996 Stuart and Neupert, 1996 Neupert, 1997 Roise, 1997). 

Clearly, there are many exceptions to this view. Theoretically, it is interesting to see how much a unifying model can explain the localization of the total set of mitochondrial proteins. 

Claros, M. (1995). MitoProt, a macintosh application for studying mitochondrial proteins. Comput. Appli Biosci. 11, 441-447. 

A.D. Presley, K.M. Fuller and E. A. Arriaga, MitoTracker Green labeling of mitochondrial proteins and their subsequent analysis by capillary electrophoresis with laser-induced fluorescence detection. J. Chromatogr.B, 793 (2003) 141-150. 

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