Nuclear genes

The majority of the peptides in mitochondria (about 54 out of 67) are coded by nuclear genes. The rest are coded by genes found in mitochondrial (mt) DNA. Human mitochondria contain two to ten copies of a smaU circular double-stranded DNA molecule that makes up approximately 1% of total ceUular DNA. This mtDNA codes for mt ribosomal and transfer RNAs and for 13 proteins that play key roles in the respiratory chain. The linearized strucmral map of the human mitochondrial genes is shown in Figure 36-8. Some of the feamres of mtDNA are shown in Table... 

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.)...

Disorders of mitochondrial oxidative phosphorylation Proteins encoded by mitochondrial genes Proteins encoded by nuclear genes... 

C Welz, W Neuhuber, H Schreier, R Repp, W Rascher, A Fahr. Nuclear gene targeting using negatively charged liposomes. Int J Pharm 196(2) 251-252, 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. 

Although iron-sulfur proteins are found in various cellular localizations in eukaryotic cells, mitochondria are the major site of Fe-S cluster biosynthesis (Lill et ah, 1999). Deletions in nuclear genes involved in mitochondrial iron-sulfur cluster formation lead to massive accumulation of iron in mitochondria (Chapter 7). For example, deletion of ATM1, a mitochondrial ATPase, which seems to be responsible for the export of Fe-S clusters, leads to respiratory incompetence, excessive iron accumulation and leucine auxotrophy (Kispal et ah, 1999). In Ayfhl cells there is only partial loss of mitochondrial Fe-S enzymes and the cells are not leucine auxotrophs. 

Mutations in one nuclear gene (ATP12), encoding an ATPase assembly protein, have been associated with complex V deficiency in an infant with congenital lactic acidosis and a rapidly fatal disorder affecting brain, liver, heart, and muscle [19]. 

D. Hahn, P. Bennoun, U. Kiick (1996) Altered expression of nuclear genes encoding thechloroplast polypeptides in non-photosynthetic mutants of Chlamydomonas... 

Today s mitochondria lack most of the genes involved in phosphohpid metabolism. Therefore, mitochondria have to import most of their hpids. Phospholipids such as phosphatidylcholine, phosphatidylserine, phosphatidylglycerol, and phosphatidylinositol must be synthesized in the endoplasmatic reticulum under the control of nuclear genes and then transferred to mitochondria (Voelker, 2000) (Figure 1). Mitochondria use both nuclear and mitochondrial encoded proteins to further diversify phospholipids (Dowhan, 1997 Kent, 1995 Daum, 1985). Thus, a nuclear phosphatidylserine decarboxylase converts phosphatidylserine into phosphatidylethanolamine, or mitochondrial encoded cardiolipin synthase converts phosphatidylglycerol into cardiolipin which is incorporated exclusively into the inner mitochondrial membrane. 

Figure 1. Control of mitochondrial biogenesis by the nuclear genome. Most mitochondrial proteins, including cytochrome c, are nuclear gene products which are subsequently imported into mitochondria. Similarly, most enzymes involved in synthesis of mitochondrial phosphoplipids are encoded in the nuclear genome. Being located in the endoplasmatic reticulum, they synthesize phosphatidylcholine (PtdCho), phosphatidylserine (PtdSer), phosphatidylglycerol (PG) and phosphatidylinositol (Ptdins). The phospholipids are transferred to the outer membrane. The imported lipids then move into the inner membrane at contact sites. Mitochondria then diversify phospholipids. They decarboxylate phosphatidylserine to phosphatidylethanolamine (PtdEtN), but the main reaction is the conversion of imported phosphatidylglycerol to cardiolipin (CL). Cardiolipins localize mainly in the outer leaflet of the inner membrane.

Mitochondrial proteins encoded by nuclear genes are translated by ribosomes free in the cytoplasm, then folded and transferred into the mitochondria by different molecular chaperones. 

All of the complexes in the respiratory chain are made up of numerous polypeptides and contain a series of different protein bound redox coenzymes (see pp. 104, 106). These include flavins (FMN or FAD in complexes I and II), iron-sulfur clusters (in I, II, and III), and heme groups (in II, III, and IV). Of the more than 80 polypeptides in the respiratory chain, only 13 are coded by the mitochondrial genome (see p. 210). The remainder are encoded by nuclear genes, and have to be imported into the mitochondria after being synthesized in the cytoplasm (see... 

Altamura N, Groudinsky O, Dujardin G, Slonimski PP (1992) NAM7 nuclear gene encodes a novel member of a family of helicases with a Zn-ligand motif and is involved in mitochondrial functions in Saccha-romyces cerevisiae. J Mol Biol 224 575-587... 

It should be born in mind that normal MRC activity can be found in an organ or a tissue that does not clinically express the disease. One might deal with a tissue-specific organ deficiency, as observed in Friedreich s ataxia where iron-sulfur deficiency is barely detectable in skeletal muscle or skin fibroblasts [57]. Tissue specificity is far from being understood it is often observed even in the case of patients harboring deleterious mutation in nuclear genes with widespread expression in the organism [9]. 

Contamine V, Picard M (2000) Maintenance and integrity of the mitochondrial genome a plethora of nuclear genes in the budding yeast. Microbiol Mol Biol Rev 64 281-315... 

A small proportion of human mitochondrial proteins (13 proteins) are encoded in the mitochondrial genome and synthesized within mitochondria. About 900 mitochondrial proteins are encoded in nuclear genes and imported into mitochondria after their synthesis. 

---