MITOCHONDRIAL MYOPATHY: AN ENERGY CRISIS IN THE CELLS

MITOCHONDRIAL MYOPATHY: AN ENERGY CRISIS IN THE CELLS
by Sharon Hesterlee




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THE MITOCHONDRIAL GENETICS MAZE
The inheritance patterns of the mitochondrial encephalomyopathies can be quite complicated. The mutations that cause these diseases can be in the chromosomes; this is what's usually meant when people talk about a genetic or inherited disease.

But mitochondrial encephalomyopathies have a unique situation. People can also inherit one of these diseases through mutations in the mitochondrial DNA (mtDNA), which comes from the mother only. Mitochondria are the only parts of the cells that have their own DNA, separate from that of the chromosomes in the cell's nucleus, called nuclear DNA.

This situation occurs because the mitochondrial respiratory chain, which is the final step in the energy-making process, is made up of proteins that come from both nuclear and mtDNA (see illustration). Although only 13 of roughly 100 respiratory chain proteins come from the mtDNA, these 13 proteins contribute to every part of the respiratory chain except complex II, and 24 other mitochondrial genes are required just to manufacture those 13 proteins. Thus, a defect in either a nuclear gene or one of the 37 mitochondrial genes can cause the respiratory chain to break down. (This respiratory chain has nothing to do with breathing.)

When mitochondrial disease is caused by defects in the nuclear DNA, the inheritance follows a "Mendelian" pattern, just as other inherited disorders do (named for Gregor Mendel, the 19th-century scientist who first explained inheritance). These inheritance patterns include autosomal dominant, autosomal recessive and X-linked. Leigh syndrome (caused by defects in complexes I and IV) is one of the most common forms of mitochondrial encephalomyopathy inherited in this fashion. It's usually autosomal recessive, meaning that two copies of the defective gene, one from each parent, are required to produce the disease.

Although nuclear DNA defects are relatively straightforward, when a disease is caused by defects in the mtDNA, it gets more complex. Mitochondrial genetics are made thornier by the fact that, instead of inheriting two copies of each mitochondrial gene (one from the father and one from the mother) in the way that nuclear genes are inherited, you inherit from your mother literally hundreds of thousands of copies of the 37 mitochondrial genes, while you inherit no mtDNA from your father. (Each of the roughly 100,000 mitochondria in the mother's egg cell may contain between two and 10 copies of the mtDNA genes.)

Also, when a mutation occurs in the mtDNA, only some of the many copies of mtDNA distributed within the mitochondria of each cell will carry the mutation -- a situation known as heteroplasmy (see illustration below). The ratio of mutant to normal mtDNA in each tissue, along with other factors, may determine the severity of the disease in an individual.