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Mitochondrial diseases are very rare. However, they are very interesting because they are genetic diseases, and yet are very different to all other types of genetic disease.
Surprisingly, there is actually DNA in the body that is not on any of the 46 chromosomes. This "other DNA" was discovered a long time ago but has only recently been linked to disease. Currently, mitochondrial DNA is an extremely active area of research.
Mitochondrial DNA is not in the chromosomes in the nucleus. Cells have not only 46 chromosomes with DNA inside the nucleus, but also have small organnelles called "mitochondria" in the cell but outside the nucleus that also have small amounts of DNA. These mitochondria are about the size of a bacteria, but are part of normal cells. There are several other types of organelles inside all cells, but only mitochondria have DNA. The best known use of mitochondria is as a cell's power plant, since it processes glucose to produce energy. A normal cell can have one or up to thousands of mitochondria, and each will have similar mitochondrial DNA.
Whereas nuclear chromosomes encode around 30,000 genes in 3 billion bases, the mitochondrial DNA genome is tiny with only around 16,500 bases. However, this 16k of data is enough to encode several proteins and RNA molecules, containing exactly 37 genes.
The 16k is also more than enough to have a few bugs in its code, including bugs in its 37 genes. Mitochondrial DNA diseases do occur through similar mutation methods as chromosome DNA diseases. They can be inherited or can occur from spontaneous mutations. However, inherited mitochondrial diseases are always inherited from the mother, not the father, because of a quirk in the egg-sperm interaction giving all the mother's mitochondria to the child. This strange maternal inheritance pattern is the case for purely mitochondrial DNA diseases. However, there are genes in the normal nuclear DNA that also affect the mitochondria, so there are many diseases that involve both nuclear and mitochondrial DNA and have more balanced inheritance patterns.
Mitochondrial DNA has become useful for not only disease diagnosis and treatment. Mitochondrial DNA has found forensic use in court as either a supplement or alternative to nuclear DNA testing. It has advantages and disadvantages: mtDNA can be extracted from smaller samples but has less distinguishing power because of its much smaller genome size.
Mitochondrial DNA has also been used by anthropologists and evolutionists. Features of mtDNA have been analyzed across populations to track movements and support theories, such as to argue that all humans derive from Africa. While forensive and anthropologic use of mtDNA is interesting, we won't dwell on it, focusing instead on buggy mtDNA code and the diseases it causes.
The inheritance pattern of mitochondrial disease is lop-sided, always coming from the mother. Mitochondrial DNA is normally maternally inherited. Paternal inheritance is extremely rare and at best a tiny part of mitochondrial inheritance. Hence, any bad mitochondrial gene usually comes from the mother.
Maternal inheritance has several features. Both males and females can get mitochondrial diseases equally, but always get it from their mother. A father cannot pass on mitochondrial disease to his children. This fact is true across multiple generations, and mitochondrial DNA comes down the long line of mothers and grandmothers.
But why is there a one-sided maternal inheritance pattern? The answer is that during reproduction, a new zygote gets all its mitochondria from the egg, not the sperm. (Perhaps it is not 100% but because the egg is huge compared to a sperm cell, and having around 1,000 mitochondria, the egg provides almost all, if not all of the mitochondria.) Cells cannot create new mitochondria. Instead, mitochondria reproduce themselves within a cell and thus all mitochondria in the body are copies of the original ones from the mother's egg.
Interestingly, some theories contend that mitochondria are actually separate life forms living in symbiosis within other cells, like a kind of helpful symbiotic internal bacteria. Other theories contend that they started this way early in evolution but then became an intrinsic part of the cell itself. In any case, mitochondria are organnelles that act somewhat independently from the cell. Cell replication (mitosis) does not replicate mitochondria but instead randomly splits the existing mitochondria between the two daughter cells. Mitochondria replicate themselves within the cell as a process separate from cell division. Unlike chromosomes, mitochondria are not split in half during the production of egg or sperm cells for reproduction. Instead, the number of mitochondria are approximately doubled in a cell prior to mitosis.
It is important to be clear what is meant by an MC disease. There are two ways the MC can be involved in a disease:
Mitochondrial diseases tend to be progressive and do not cause symptoms early in life. Why are MC diseases progressive? Possibly as more and more MC get "infected" (like a virus infection inside bacteria?). Perhaps there are many mitochondrial diseases but only those that result in "bad mitochondria" that grow excessively and beat out the "good mitochondria" actually cause a disease. Other less virulent mitochondrial disorders might simply remain a small minority of the population. This kind of idea makes sense as human zygotes inherit multiple mitochondria from their mother.
Mitochondrial disease affects cells differently. Not surprisingly, the cells that need the most energy and have the most mitochondria are also the most likely to be affected by mitochondrial diseases: brain and central nervous system, heart, muscle, kidneys, and endocrine glands.
Mitochondrial diseases affect everyone differently. Even mtDNA inherited diseases have massively different effects on each patient. This feature of mtDNA diseases is much different from nuclear DNA inherited diseases, in which a recessive disease usually has great similarity in all patients. One of the best theories of this variability of inherited mtDNA diseases is that not everyone gets the mutation in the same amounts. An egg cell has around 1,000 mitochondria, and some percentage of these may have the mtDNA disease. The exact percentage is a random event. Patients who inherit a large percentage of bad mitochondria will get the disease earlier and more severely. Those with a lower percentage will have other good compensating mitochondria that will either mitigate the severity of the disease or delay its onset or both.
Examples of mitochondrial DNA diseases:
Another disease related to mitochondria is Wolfram's disease. Wolfram's disease is not a mitochondrial DNA disease, since it is a genetic disease of chromosome 4. However, this non-mitochondrial disease does cause damage to mitochondrial DNA.
Some cancer forms are caused by mutations of mitochondrial DNA.
The best known use of the mitochondria is as a "power house" since they perform glucose oxidation to convert glucose into energy for the cell to use for other reactions. Mitochondria contain enzymes that catalyze the various steps of the glucose reaction. Mitochondria make around 90% of the body's energy. For this reason, cells that need lots of energy tend to make more copies of MC than less energy intensive cells.
However, energy production is not the only purpose of MC. In fact, they have numerous specialized functions depending on what type of cell they are present in.
The MC DNA genome has been completely mapped. Although everyone's MC DNA is slightly different, the variations are fairly well described. The standard Cambridge sequence has 16548 bases in total.
The DNA in mitochondria uses the same 4 bases: ACGT. The pairing maps in the double strands remain the same as nuclear DNA with maps: AT and CG.
Genes and their function are similar in mitochondria and nuclear DNA. Proteins are encoded by DNA and are created via the DNA->RNA->Protein sequence. In fact, mtDNA protein encoding is simpler because there are no introns or exons. Triplets are used to represent amino acids and start or stop codons. However, mitochondrial DNA has a slightly different encoding for the triplet codons that represent the amino acids that form proteins:
Of the 64 possible codes, there are only 4 differences between mtDNA and the usual code in nDNA:
The physical structure of mtDNA is simlar to nDNA. It is double-stranded. However, mtDNA is circular rather than a spiral. However, non-circle forms of mtDNA have been seen although less commonly. Circular DNA structure is not uncommon in nature, being common in the DNA of bacteria and other single celled organisms in the class of prokaryotes.
The entire human mitochondrial DNA sequence has been mapped quite easily, being only 16k. In fact, this has been done completely and a great deal of research has occurred on the various genes and non-gene sequences in mtDNA.
There are exactly 37 genes in mtDNA: 13 encode proteins, 2 rRNA, and 22 tRNA. The 13 proteins are also required within the MC itself and are all part of the main function of the MC: processing glucose using the oxidative phosphorylation pathway. This makes sense for the MC to make products that it needs. Some of the proteins would otherwise be difficult to get through the membrane into the MC as they are almost insoluble.
The majority of mtDNA is encoding data sequences. There is relatively little control DNA in mtDNA and little space between genes.
mtDNA is more prone to mutation that nuclear DNA. The mitochondria has less DNA repair capability as a mutation defense. In fact, the high rate of mutation over generations in a particular control area of mtDNA is the reason that forensic and anthropological analysis of mtDNA is practical despite its tiny genome size. mtDNA also lacks the comment-like introns in encoding sequences, so all gene mutations will directly affect the protein encoding.
Free radicals may be one cause of mtDNA mutations. An interesting vicious cycle can also arise: a mutated mitochondria reduces its energy production which in turn actually causes more free radicals and more mtDNA damage.
Mutated mitochondria also seem to be selectively amplified within the body. For some reason mutated mitochondria often seem to have an advantage over "good" mitochondria.
There are several features of mitochondrial diseases that are suspiciously similar to various age-related diseases and even aging itself. These disease characteristics include:
Examples of diseases that also have these patterns include the classic diseases of aging:
Obviously this pattern is not strong evidence of a link, and much research has examined mitochondria in the elderly and those with diseases. Also, since none of these diseases have a pure maternal inheritance pattern (though perhaps somewhat maternally skewed), this would indicate the diseases, even if caused by the mitochondria, are certainly not pure mitochondrial DNA diseases. The known mutations of the 37 genes do not cause these classic diseases. For example, though an mtDNA mutation does cause "diabetes with deafness", a rare subset of Type 2 diabetes, none are found to cause classic Type 2 diabetes. This lack of a clear link would also seem to rule out spontaneous mtDNA mutations as the sole cause of these classic diseases. Hence, if the diseases do involve the mitochondria, it is probably via a complex interplay between nuclear and mitochondrial DNA inheritance and/or spontaneous mutations.
Some evidence of mtDNA mutations involved in classic aging diseases has been found. For example, 5% of Alzheimer's patients have a particular mtDNA mutation. This is much higher than the general population, and might indicate the involvement of mtDNA in a subset of Alzheimer's patients. However, no smoking gun of 100% has been found for any particular mtDNA mutation, and we would not expect one since none of these diseases have pure maternal inheritance. Instead, general evidence of increased and varied mtDNA mutations has been found in older or diseased groups. Hence, mtDNA mutation accumulation might be a factor in the decline of function in various cells as part of aging or diseases. Furthermore, such mtDNA mutations might combine with predispositive nuclear DNA mutations (inherited or spontaneous) in causing age-related diseases.
A link between mitochondria and Type 2 diabetes seems particularly plausible, given the clear defect in some aspect of glucose metabolism in which the mitochondria are central players. However, there is no particular mtDNA mutation that causes Type 2 diabetes, nor do all Type 2 diabetes share a particular mtDNA mutation. At best there is a subset of Type 2 diabetes patients that are caused by mtDNA mutations (quoted as 2%), usually with the "diabetes with deafness" syndrome.
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