Rather than being completely controlled by the cell nucleus, mitochondria contain their own genome. Though this genome is tiny, only containing 37 genes in human cells, it is believed to have once contained more genes that were eventually lost to the nucleus over evolution – this means that many mitochondrial proteins are now encoded within the nucleus. Aerobic (using oxygen) respiration via mitochondria requires different complexes composed of multiple proteins; most of these contain proteins encoded by both the nuclear and mitochondrial genomes, which means both nuclear and mitochondrial genomes are needed for respiration.
Unlike nuclear DNA, mitochondrial DNA is only inherited maternally. Mechanisms of this uniparental inheritance (from one parent only) have been debated. Dilution effects have been suggested, in which the female gamete contains an extremely large number of mitochondria while the male gamete has limited mitochondria. This would mean that, when these two cells fuse together, almost all the mitochondria (and the DNA they contain) in the resulting embryonic cell are from the oocyte, making the paternal contribution negligible. However, this explanation has been criticised as over-simplified, and evidence has been found of paternal mitochondria being actively destroyed in the fertilisation process. Another topic of heated debate is how and why uniparental inheritance of mitochondria evolved!
Mitochondrial diseases occur due to inadequate mitochondrial functioning, which can be caused by mutations in the mitochondrial DNA. As the ATP demands of higher organisms such as humans cannot be met by anaerobic respiration (not using oxygen) in the cytoplasm alone, mutations decreasing the efficiency of mitochondrial respiration can lead to diseases. Some examples of mitochondrial diseases are Leber hereditary optic neuropathy (LHON), age-related hearing loss and myoclonic epilepsy with ragged-red fibres (MERRF).
However, mitochondrial disease is more complicated than disease being present if certain gene mutations are present. People contain different populations of mitochondria with different DNA, both within the same cell and different cells. Disease presence, tissue-specific symptoms and severity depend on the proportion of healthy to defective mitochondria. Mitochondrial disease occurs if a certain threshold of defective mitochondria is reached. A female with cells containing both healthy and defective mitochondria but below the disease threshold, may produce an oocyte with a higher proportion of defective mitochondria, resulting in a child with a mitochondrial disease from an apparently healthy female. Also, individuals with the same mitochondrial DNA mutation will display different severities based on proportions of healthy to defective mitochondria.
When the embryo cell divides to produce the zygote, the segregation of different mitochondria may not be even, so some tissues may receive more faulty mitochondria than others. This can explain why, in mitochondrial diseases that can affect multiple tissues, an individual with one mutation may display symptoms in some tissues, but an individual with that same mutation may display symptoms in different tissues. Also, mitochondrial disease thresholds differ between cell types, based on the ATP requirements of that cell. The threshold is lower for energy-intensive tissues, explaining why mitochondrial diseases mostly affect the brain, eyes, ears, muscles and heart.
Gene mutations accumulate throughout an organism’s lifespan – mitochondrial DNA are especially vulnerable to this, due to less capable repair mechanisms and their constant production of molecules that have the potential to induce mutations. Therefore, mitochondrial diseases often worsen or arise during aging. In addition, gene expression can be modified without changing the genetic code, a phenomenon referred to as epigenetics. Epigenetics is mostly studied in nuclear DNA, but this can occur in mitochondrial DNA as well, and could affect mitochondrial functioning.
Mitochondrial DNA can be use medically, perhaps most notably in assistive reproductive technologies (ART). Fertility issues may be caused by insufficient mitochondria in oocytes (below 100,000 can be considered inviable), so increasing the number of functional mitochondria in the oocyte may increase the egg’s chance of surviving. This can be carried out via transferring the cytoplasm of the oocyte from a healthy donor oocyte (or perhaps from a patient oocyte). This technique has been used since the late 1990s, resulting in healthy offspring.
A more recent development, however, is mitochondria replacement – resulting in what have commonly been referred to as ‘three-parent babies’. The UK became first country to legalise this, allowing females with known mitochondrial diseases to have mitochondrial disease-free children, by replacing the defective mitochondria with those from a healthy donor. Two different methods may be used: spindle transfer involves fusing the chromosomes of the female’s unfertilised egg to the unfertilised egg on the healthy donor female (which has had its chromosomes removed), while pro-nuclear transfer transfers nuclear DNA from the patient’s fertilised egg to the fertilised egg of the donor (which has had its nuclear DNA removed).
However, it has been suggested that some defective mitochondrial DNA may persist in the embryos produced, and replication of this DNA may occur to increase the population of defective mitochondria. If this occurs, mitochondrial disease thresholds may be reached as mutations accumulate during aging. While some mitochondrial genomes appear to be preferentially replicated, our understanding of how these genomes are chosen is largely incomplete. Therefore, while mitochondrial replacement is a ground-breaking development, we cannot be sure of its long-term implications and risks.