Topics and Speakers Salvatore DiMauro, MD
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Synopsis
Mitochondria are the bacteria-derived organelles which power the metabolic activity of all cells in the body by producing energy in the form of ATP. However, small changes in the makeup of these organelles can cause fatal diseases with multisystemic symptoms. In this lecture, Dr Salvatore DiMauro discusses the function and characteristics of mitochondria, the non-Mendelian and Mendelian sources for mitochondrial diseases, defects in protein synthesis and protein-coding genes and their consequences, defects in intergenomic communication and mitochondrial behavior and their consequences, and current therapies.
ATP comes from two types of cell fuels: carbohydrates and fatty acids. When they are used in the beta-oxidation pathway, the end result is acetyl coenzyme A. This molecule is fed into the Krebs cycle, which in turn produces energy currency molecules (NADH and FADH2) that are fed into the electron transport chain (ETC). It is in the ETC where the mitochondrial DNA comes in. Dr DiMauro states that the ETC is the only pathway in the cell where two genomes, mitochondrial and nuclear, are needed. Hence, mutations in either genome can cause mitochondrial disorders.
Mitochondrial DNA differs from nuclear DNA in three important ways: it is only 16.5 kb; it is very dense; and it undergoes continuous mutations at a much higher rate than nuclear DNA. Mitochondrial genetics are non-Mendelian by nature as can be seen by the following two ways in which they are transmitted from parent to offspring. Even though we get all nuclear genetic information from both parents, mitochondrial DNA information comes only from the mother. Hence, the first characteristic is maternal inheritance. The second characteristic is heteroplasmy and the resulting threshold effect. Heteroplasmy occurs when, within a single cell, there is a mixture of mitochondria, some containing mutant DNA and some containing normal DNA. Once you have a mutation in mitochondrial DNA, all cells in the body will contain mutated DNA. This is why mitochondrial diseases are multisystemic-because mitochondria are in all tissues. However, because different tissues have different energy needs, the percentage of the mutation needed to cause problems varies. This critical level is the threshold effect.
There are three defects in mitochondrial genetics that cause disorders: deletions in the mitochondrial DNA itself, mutation in tRNA genes, and mutations in protein-coding genes in nuclear DNA. Mitochondrial DNA deletions can cause diseases such as Kearns-Sayre syndrome, which causes progressive limitation of eye movement, and Pearson's syndrome, which causes anemia and neutropenia. Mutations in tRNA genes can cause mitochondrial encephalomyopathy lactic acidosis (MELAS), whose main symptom is strokes and migraines in children and young adults. Mutations in protein-coding genes can cause Leber's hereditary optic neuropathy, which leads to blindness in young adults. Sadly, even though current medicine has identified the mutations and their locations, the pathogenesis of these diseases remains unknown. The most common source of mitochondrial disorders is mutations in the protein-coding genes in nuclear DNA. These disorders follow a Mendelian inheritance and are more common since the nuclear genome exerts overarching control over the cell. The simplest form of mitochondrial disorders is caused by mutations in the respiratory chain subunits. Dr DiMauro details complexes that are mutated in the respiratory chain.
Other sources of mitochondrial disorders include defects in intergenomic communication and in mitochondrial behavior. When the nuclear genome and mitochondrial genome miscommunicate, this can result in three consequences: multiple deletions of mitochondrial DNA, depletion of mitochondrial DNA, or defective translation. For instance, a patient with very little mitochondria would die of respiratory failure. Defects in mitochondrial behavior, such as problems with mitochondrial motility, fusion, or fission, may also result in diseases. For instance, autosomal dominant optic atrophy is caused by a problem in protein involved in mitochondrial motility. Interestingly enough, mitochondria may be involved in the pathogenesis of known diseases such as Parkinson's, since they control apoptosis.
Dr DiMauro concludes the lecture with two possible approaches for mitochondrial disorders. The first one, which he terms a "palliative approach," entails simply giving the patient a cocktail of vitamins and cofactors, such as CoQ 10 and carnitine; the second involves using in vitro fertilization with a donor's mitochondrial genome. In this latter approach, the baby would have the nuclei of the parents and the mitochondrial genome from a donor. This approach has been quite controversial. Although these two methods offer a chance to improve the conditions of mitochondrial disorder, it remains a challenge to treat.
