Genes mitochondrial diseases

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). 

Mitochondrial diseases are often expressed as neuropathies and myopathies because brain and muscle are highly dependent on oxidative phosphorylation. Mitochondrial genes code for some of the components of the electron transport chain and oxidative phosphorylation, as well as some mitochondrial tRNA molecules. 

It is important to emphasise that only the head of the sperm enters, so that it is only the nuclear genetic material that enters the ovum, that is, the genetic material in the mitochondria of the sperm does not enter the ovum and hence it does not appear in the zygote. Consequently, mitochondrial genes are inherited only from the mother. This has implications for some mitochondrial diseases (Chapter 9). 

Mitochondrial diseases are caused by mutations in various mtDNA-encoded genes, most of which result in defective mitochondrial protein synthesis. 

A mutation in any of the 13 protein subunits, the 22 tRNAs, or the two rRNAs whose genes are carried in mitochondrial DNA may possibly cause disease. The 13 protein subunits are all involved in electron transport or oxidative phosphorylation. The syndromes resulting from mutations in mtDNA frequently affect oxidative phosphorylation (OXPHOS) causing what are often called "OXPHOS diseases."3-6 Mitochondrial oxidative phosphorylation also depends upon 100 proteins encoded in the nucleus. Therefore, OXPHOS diseases may result from defects in either mitochondrial or nuclear genes. The former are distinguished by the fact that they are inherited almost exclusively maternally. Most mitochondrial diseases are rare. However, mtDNA is subject to rapid mutation, and it is possible that accumulating mutants in mtDNA may be an important component of aging.h k... 

Mutations in Nuclear Genes and Animal Models of Mitochondrial Diseases... 106... 

Point Mutations in rRNA/tRNA Genes of mtDNA Associated with Mitochondrial Diseases 2... 

In 1995, Bourgeron et al. (B7) first reported that mutation in a nuclear gene coding for succinate dehydrogenase may result in mitochondrial disease. In 1998,... 

Mitochondrial Disease and Cancer Mutations in the genes that encode certain mitochondrial proteins are associated with a high incidence of some types of cancer. How might defective mitochondria lead to cancer ... 

Treatment of most patients with genetic mitochondrial diseases has been disappointing and has usually been approached in a sporadic, uncontrolled manner. There is no proven therapy for patients with PDC deficiency. Current strategies rely on nutritional or pharmacological interventions or both to improve patient quality of life. Recent studies have also begun to address the potential role of gene transfer for Ela defects. 

Mitochondrial disease. A mutation in a mitochondrial gene encoding a component of ATP synthase has been identified. People who have this mutation suffer from muscle weakness, ataxia, and retinitis pigmentosa. A tissue biopsy was performed on each patient, and submitochondrial particles were isolated that were capable of succinate-sustained ATP synthesis. First, the activity of the ATP synthase was measured on the addition of succinate and the following results were obtained. 

Mitochondrial disease. A mutation in a mitochondrial gene encoding a component ol A I P synthase has been identified. People who have this mutation sulfer Irom muscle weakness, ataxia, and... 

In a comprehensive study in which hereditary and mitochondrial diseases had been excluded, 97 out of approximately 1000 genes were detected to possess single gene mutation related to metabolic diseases [72]. When the product categories of these abnormal phenotype related genes were analyzed, the most frequently detected ones were metabolism-related enzymes, 31.2% and modulatory proteins, 13.6% and the less frequently detected ones, <10%, were receptors, transcription factors, intracellular and extracellular matrix compounds, and the others. 

Mitochondrial diseases are a broad group of disorders affecting the function of the electron transport chain, proliferation of mitochondria, or transport of molecules into mitochondria to enable function. There are over 200 specific disorders involving over 1,000 genes, both in the nuclear DNA and the circular mitochondrial DNA (mtDNA) found in multiple copies within... 

Adapted from Harding AE Neurological disease and mitochondrial genes.Trends Neurol Sci 1991 14 132. 

---