Mitochondrial Genetics

Mitochondria contain their own DNA (mitochondrial DNA), which is separate from the DNA contained in the cell nucleus. Unlike nuclear DNA, which is in herited from both parents, mitochondrial DNA (mtDNA) is inherited exclusively from the mother's ovum. The mitochondrial genome (16,569 bp) is tiny compared with the nuclear genome (3 X 109 bp). The mitochondrial genome encodes 24 ri-bosomal RNAs, 22 transfer RNAs, and 13 genes coding for subunits of the respiratory chain. The remaining mitochondrial proteins are encoded by nuclear genes. These characteristics result in some unusual genetic and clinical features.

1. Heteroplasmy

Because there are hundreds of mitochondria per cell, when a mutation arises in mtDNA, that mitochondrion and its descendants contain the mutation, but they coexist with other, normal mitochondria—a situation termed heteroplasmy. When the cell divides, the mitochondria are partitioned between the daughter cells, which may receive varying percentages of normal and mutant mitochondria.

2. Threshold Expression

Different organs in the human body have different requirements for mitochondrial energy metabolism. It is generally agreed that the brain, heart, and skeletal muscle have the highest energy demands followed by the kidneys, endocrine system, and liver (34). The phenotypic expression of a pathological mtDNA mutation will be determined by the relative proportion of wild-type versus mutant mitochondria in a given tissue. The percentage of mutant mtDNAs needed to impair energy metabolism enough to cause organ dysfunction is called the threshold effect (35).

3. Mitochondrial Mutation Rate

The mutation rate in mitochondrial DNA is significantly higher than that observed in nuclear genes. The accumulation of sequence polymorphisms has been estimated to occur 17 times faster in mtDNA than in nuclear DNA (36,37). This has been attributed to the generation of free radicals from oxidative phosphorylation (which causes DNA damage) as well as to the paucity of DNA repair mechanisms in mitochondria as compared with the nucleus (38).

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