Mitochondrial machinery

Similarly, abnormalities in the mitochondrial machinery and resulting oxidative stress may also intervene in Parkinson s disease (PD) [31, 32]. The decreased activity of mitochondrial complex I in PD patients [33], and the preferential toxicity of the complex I inhibitor rotenone [34] and MPP+ (the active metabolite of MPTP)... 

Kaut A, Lange H, Diekert K, et al. 2000. Isalp is a component of the mitochondrial machinery for maturation of cellular iron-sulfur proteins and reqnires conserved cysteine residues for function. J Biol Chem 275 15955-61. 

As discussed before, the energy conserved by the mitochondrial machinery in the molecule of ATP, or as a different form of biological energy, can be finally utilized for endoergonic processes muscular contraction, osmotic work, etc. 

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. 

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). 

The biogenic amines are the preferred substrates of MAO. The enzyme comes in two flavors, MAO-A and MAO-B, both of which, like FMO, rely on the redox properties of FAD for their oxidative machinery. The two isoforms share a sequence homology of approximately 70% (81) and are found in the outer mitochondrial membrane, but they differ in substrate selectivity and tissue distribution. In mammalian tissues MAO-A is located primarily in the placenta, gut, and liver, while MAO-B is predominant in the brain, liver, and platelets. MAO-A is selective for serotonin and norepinephrine and is selectively inhibited by the mechanism-based inhibitor clorgyline (82). MAO-B is selective for /1-phcncthylaminc and tryptamine, and it is selectively inhibited by the mechanism-based inhibitors, deprenyl and pargyline (82) (Fig. 4.32). Recently, both MAO-A (83) and MAO-B (84) were structurally characterized by x-ray crystallography. 

Based on the intrinsic mitochondriotropism of dequalinium and its unique self-assembly behavior, we have developed a strategy for direct mitochondrial transfection (47-49), which involves the transport of a DNA-mitochondrial leader sequence (MLS) peptide conjugate to mitochondria using DQAsomes, the liberation of this conjugate from the cationic vector upon contact with the mitochondrial outer membrane followed by DNA uptake via the mitochondrial protein import machinery. We have demonstrated that DQAsomes fulfill all essential prerequisites for a mitochondria-specific DNA delivery system they bind and condense pDNA (24), protect it from... 

Ered Sanger, a double Nobel Prize winner, sequenced the human mitochondrial genome back in 1981. This genome codes for 13 proteins and the mitochondrion possesses the genetic machinery needed to synthesize them. Thus, the mitochondria are a secondary site for protein synthesis in eukaryotic cells. It turns out that the 13 proteins coded for by the mitochondrial genome and synthesized in the mitochondria are critically important parts of the complexes of the electron transport chain, the site of ATP synthesis. The nuclear DNA codes for the remainder of the mitochondrial proteins and these are synthesized on ribosomes, and subsequently transported to the mitochondria. 

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... 

The outcome of, or perhaps the support for, the endosymbiont transferring its genes to the nucleus was the evolution of new machinery in the eukaryotic cell to send the nuclear-encoded proteins back to the degenerate endosymbiont to allow the latter to function. Moreover, it is of note that the large majority of extant mitochondrial proteins are not of endosymbiotic or a-proteobacterial origin. These proteins have either been recruited... 

It has been hypothesized that the process of inventing a protein import machine for mitochondria would have been so intricate and critical that it is unlikely to have occurred more than once (CavaUer-Smith 1987). By extension, similarities found between mitosomal and hydrogenosomal and mitochondrial protein import have been presented as strong support that all these organelles use common components for import, and are therefore one and the same. These observations have prompted a number of experimental and bioinformatics studies to shed light on the constitution and evolution of the protein import machineries of hydrogenosomes and mitosomes. 

Two major protein import machineries have been characterized to date in the mitochondrial outer membrane the TOM and the SAM complexes (Fig. 1). 

Bohnert M, Pfanner N, van der Laan M (2007) A dynamic machinery for import of mitochondrial precursor proteins. FEBS Lett 581 2802-2810 Bolliger L et al. (1994) A mitochondrial homolog of bacterial GrpE interacts with mitochondrial hsp70 and is essential for viability. EMBO J 13 1998-2006... 

Dekker PJ, Keil P, Rassow J, Maarse AC, Pfanner N, Meijer M (1993) Identification of MIM23, a putative component of the protein import machinery of the mitochondrial inner membrane. FEBS Lett 330 66-70... 

Kozjak V et al. (2003) An essential role of Sam50 in the protein sorting and assembly machinery of the mitochondrial outer membrane. J Biol Chem 278 48520-48523... 

Pfanner N, Geissler A (2001) Versatility of the mitochondrial protein import machinery. Nat Rev Mol Cell Biol 2 339-349... 

A characterization of the translocase complexes responsible for mitosomal protein import in Giardia is under way. An iterative BLAST search of the G. intestinalis genome was employed for the identification of the import machinery components. The only candidate to have been found so far is GiPAMIS, a mitosomal protein homologous to mitochondrial presequence translocase-associated motor 18 (Dolezal et al. 2005). 

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