mtDNA mutations
Genetic disorders with mitochondrial inheritance are those caused by mutations in the mitochondrial DNA. Mitochondrial DNA (often shorten to mtDNA) is contained in mitochondria, which are small organelles whose task is cellular respiration.
An unknown number of chromosomes
Mitochondrial DNA is made of many small circular double-stranded DNA molecules, called mitochondrial chromosomes (if you want to learn more, read the page on the mitochondrial genome). Unlike nuclear DNA, where the chromosome number is fixed (each somatic cell has 46 chromosomes), mitochondrial chromosomes have an undefined number of copies. Because of this phenomenon, which takes the name of “polyplasmy“, mitochondrial inheritance does not follow Mendelian inheritance rules (which, by definition, includes only autosomal recessive, autosomal dominant, and X-linked inheritance).
Only inherited by the mother
Mitochondrial DNA is almost exclusively of maternal origin, since spermatozoa contain very few mitochondria, whose contribution is completely negligible. For this reason, genetic disorders with mitochondrial inheritance can be only transmitted by the mother, and never by the father. Males and females can be equally affected, but only females can transmit the mutation to the offspring.
Mitochondrial inheritance and mitochondrial disease: they are not the same
It’s really important to highlight that the sentence “genetic disorder with mitochondrial inheritance” is not the same as “mitochondrial genetic disease“. Mitochondrial genetic disease is a condition due to an alteration in the function of mitochondria and can be caused by (1) mtDNA mutation or (2) nuclear DNA mutation (in this case it follows the Mendelian inheritance rules).
Homoplasmy and heteroplasmy
In normal conditions, mtDNA molecules are homoplasmic, that is they are all identical. However, when a mutation is present, it is often present in heteroplasmy, that is, only in some and not in all mitochondrial chromosomes. Usually, homoplasmy for a disease mutation could even be not viable. Individuals with a heteroplasmic mutation may be affected or healthy carriers. Indeed, the disease becomes clinically manifest only when the number of mutated mitochondrial chromosomes overcomes a specific threshold, called critical mutational load threshold.
Bottleneck event
Bottleneck is a phenomenon in which the number of mitochondrial chromosomes that reproduce decreases more and more during oogenesis (the development of oocytes in women). In fact, during oogenesis, only the best mitochondrial chromosomes tend to reproduce, in order to select the genetic information that could be transmitted to the offspring.
For more information: 10 frequently asked questions about mitochondrial inheritance
