MITOCHONDRIAL DNA: CHARACTERISTICS, FUNCTIONS, INHERITANCE, DISEASES - BIOLOGY - 2025

The mitochondrial DNA is a small circular DNA molecule that is located inside these organelles in eukaryotic cells. This small genome codes for a very limited number of proteins and amino acids within the mitochondria. It is common to find the name "mitochondrial DNA" abbreviated in many textbooks and scientific articles as "mtDNA" or in English "mtDNA".

Mitochondria are essential organelles for eukaryotic cells, since they are responsible for transforming the energy from food consumed in the form of sugars into a form of energy that cells can use (ATP, for example).

Mitochondrial DNA (Source? National Human Genome Research Institute, via Wikimedia Commons)

All cells in eukaryotic organisms have at least one mitochondrion inside them. However, there are cells such as heart muscle cells and skeletal muscle cells that can have hundreds of mitochondria inside them.

Mitochondria have their own protein synthesis apparatus independent of the cell apparatus, with ribosomes, transfer RNAs, and an aminoacyl RNA transferase-synthetase from the interior of the organelle; although ribosomal RNA is smaller than that of the cell that houses them.

Such an apparatus shows great similarity to the apparatus of protein synthesis of bacteria. Furthermore, as in prokaryotes, this apparatus is extremely sensitive to antibiotics, but very different from that of protein synthesis in eukaryotic cells.

The term "mitochondria" was introduced by Benda at the end of the 12th century and the theory of "endosymbiosis" is the most widely accepted about its origin. This was published in 1967 by Lynn Margulis, in the Journal of Theoretical Biology.

The theory of "endosymbiosis" places the origin of the mitochondria millions of years ago. It is theorized that a cellular ancestor of eukaryotic cells “engulfed” and incorporated a bacterial-like organism into its metabolism, which later became what we now know as mitochondria.

characteristics

In mammals, generally the entire genome that comprises mitochondrial DNA is organized in a circular chromosome of 15,000 to 16,000 pairs of nucleotides or, what is the same, of 15 to 16 Kb (kilobases).

Inside most mitochondria you can get multiple copies of the mitochondrial chromosome. In human somatic cells (non-sex cells) it is common to find at least 100 copies of the mitochondrial chromosome.

In higher plants (angiosperms) the mitochondrial DNA is usually much larger, for example, in the maize plant the circular chromosome of the mitochondrial DNA can measure up to 570 Kb.

Mitochondrial DNA occupies about 1% of the total DNA of the somatic cells of most vertebrate animals. It is a highly conserved DNA in the animal kingdom, contrary to what is observed in plants, where there is a wide diversity.

In some "giant" eukaryotic cells such as ovules (female sex cells) of mammals or in cells containing many mitochondria, mitochondrial DNA can make up up to 1/3 of total cellular DNA.

Mitochondrial DNA has some different properties than nuclear DNA: it has a different density and ratio of guanine-cytosine (GC) and adenine-thymine (AT) base pairs.

The GC base pair density in mitochondrial DNA is 1.68 g / cm3 and the content is 21%; while in nuclear DNA this density is 1.68 g / cm3 and the content is around 40%.

Features

Mitochondrial DNA possesses at least 37 genes that are essential for the normal function of the mitochondria. Of those 37, 13 possess the information to produce the enzymes involved in oxidative phosphorylation.

These 13 genes encode for 13 polypeptide components of the enzyme complexes that belong to the electron transport chain and are located in the inner membrane of the mitochondria.

Despite the 13 polypeptides that mitochondrial DNA contributes to the electron transport chain, it is made up of more than 100 different polypeptides. However, these 13 components are essential for oxidative phosphorylation and the electron transport chain.

Schematic of mitochondrial DNA (Source: Mikibc ~ commonswiki, via Wikimedia Commons)

Among the 13 polypeptides that are synthesized from mitochondrial DNA, the I, II and III subunits of the cytochrome C oxidase complex and the VI subunit of ATPase pumps embedded in the internal membrane of the organelle stand out.

The information necessary for the synthesis of the rest of the components that make up the mitochondria is encoded by nuclear genes. These are synthesized in the cytoplasm like the rest of the cellular proteins and then imported into the mitochondria thanks to specific signals.

In oxidative phosphorylation, oxygen and sugar atoms such as glucose are used for the synthesis or formation of adenosine triphosphate (ATP), which is the chemical species used by all cells as a source of energy.

The remaining mitochondrial genes have the instructions for synthesizing transfer RNAs (tRNAs), ribosomal RNAs, and the enzyme aminoacyl-RNA transferase-synthetase (tRNA), necessary for protein synthesis within the mitochondria.

Heritage

Until relatively recently it was thought that mitochondrial DNA was transmitted exclusively through maternal inheritance, that is, by direct descent from the mother.

However, an article published by Shiyu Luo and colleagues in the journal Proceedings of the National Academy of Sciences of the United States of America (PNAS) in January 2019, found that in rare cases mitochondrial DNA can be inherited from both parents, both of the father as of the mother.

Before the publication of this article, it was a fact for scientists that the Y chromosome and mitochondrial DNA were inherited intact from the father and mother, respectively, to the offspring.

The “intact” inheritance of the genes of the Y chromosome of the mitochondrial genes implies that said genetic material does not undergo changes by recombination and, over the years, they only vary due to spontaneous mutations, so the variation is quite low.

Because of this, most population mobilization studies are done on the basis of these genes, since, for example, it is easy for geneticists to construct family trees using mitochondrial DNA.

Much of human history has been reconstructed through the genetic history of mitochondrial DNA. Many business houses even offer to clarify the family bond of each living person with their ancestors through techniques that study these characteristics.

Replication

The first model of mitochondrial DNA replication was proposed in 1972 by Vinograd and collaborators and this model is still valid, with some changes. Broadly, the model is based on a one-way replication that begins at two different origins of replication.

Scientists classify the mitochondrial chromosome into two different chains, the heavy chain, H or OH, from English “heavy” and light chain, L, or OL from English “light”. These are identified and located in the two unassigned open reading frames (URF) on the mitochondrial chromosome.

The replication of the mitochondrial genome begins in the heavy chain (OH) and continues in one direction until the full length of the light chain (OL) is produced. Subsequently, proteins called "mitochondrial single-stranded DNA binding proteins" are attached to protect the chain that functions as "parent" or "template."

The enzymes responsible for the separation for replication to occur (replicacosome) pass to the light band (OL) and a loop structure is formed that blocks the binding of mitochondrial single-stranded DNA binding proteins.

In this loop the mitochondrial RNA polymerase binds and the synthesis of the new primer begins. The transition to heavy chain (OH) synthesis occurs 25 nucleotides later.

Right at the time of transition to the heavy chain (OH), mitochondrial RNA polymerase is replaced by mitochondrial replicative DNA polymerase at the 3 'end, where replication initially began.

Finally, the synthesis of both chains, both heavy (OH) and light (OL) proceeds continuously until two complete circular molecules of double-stranded (double-stranded) DNA are formed.

Related diseases

There are many diseases related to a malfunction of the mitochondrial DNA. Most are caused by mutations that damage the sequence or information contained in the genome.

Hearing loss relative to increasing age

One of the best studied diseases that has been directly related to changes in the mitochondrial DNA genome, is hearing loss due to increasing age.

This condition is the product of genetic, environmental, and lifestyle factors. As people age, mitochondrial DNA accumulates harmful mutations, such as deletions, translocations, inversions, and more.

Damage to mitochondrial DNA is caused mainly by the accumulation of reactive oxygen species, these are by-products of energy production in the mitochondria.

Mitochondrial DNA is especially vulnerable to damage, as it does not have a repair system. Therefore, changes caused by reactive oxygen species damage mitochondrial DNA and cause the organelle to malfunction, causing cell death.

The cells of the inner ear have a high demand for energy. This demand makes them especially sensitive to mitochondrial DNA damage. These damages can irreversibly alter the function of the inner ear, leading to a total loss of hearing.

Cancers

Mitochondrial DNA is especially sensitive to somatic mutations, mutations that are not inherited from parents. These types of mutations occur in the DNA of some cells throughout a person's life.

There is evidence that links mitochondrial DNA alterations resulting from somatic mutations with certain types of cancer, tumors in the mammary glands, in the colon, in the stomach, in the liver and in the kidney.

Mutations in mitochondrial DNA have also been associated with blood cancers such as leukemia, and lymphomas (cancer of the cells of the immune system).

Specialists link somatic mutations in mitochondrial DNA with an increase in the production of reactive oxygen species, factors that increase mitochondrial DNA damage and create a lack of control in cell growth.

Little is known about how these mutations increase the uncontrolled cell division of cells and how they end up developing as cancerous tumors.

Cyclic vomiting syndrome

Some cases of cyclical vomiting, typical of childhood, are believed to be related to mutations in mitochondrial DNA. These mutations cause recurring episodes of nausea, vomiting, and tiredness or lethargy.

Scientists associate these vomiting episodes with the fact that mitochondria with damaged mitochondrial DNA can affect certain cells of the autonomic nervous system, affecting functions such as heart rate, blood pressure and digestion.

Despite these associations, it is not yet clear how changes in mitochondrial DNA cause recurrent episodes of cyclic vomiting syndrome.

References

1. Clayton, D. (2003). Mitochondrial DNA replication: what we know. IUBMB life, 55 (4-5), 213-217.
2. Falkenberg, M. (2018). Mitochondrial DNA replication in mammalian cells: overview of the pathway. Essays in biochemistry, 62 (3), 287-296.
3. Giles, RE, Blanc, H., Cann, HM, & Wallace, DC (1980). Maternal inheritance of human mitochondrial DNA. Proceedings of the National Academy of Sciences, 77 (11), 6715-6719
4. Luo, S., Valencia, CA, Zhang, J., Lee, NC, Slone, J., Gui, B, & Chen, SM (2019). Reply to Lutz-Bonengel et al.: Biparental mtDNA transmission is unlikely to be the result of nuclear mitochondrial DNA segments. Proceedings of the National Academy of Sciences, 116 (6), 1823-1824.
5. McWilliams, TG, & Suomalainen, A. (2019). Fate of a father's mitochondria. Nature, 565 (7739), 296-297.
6. National Library of Medicine. Genetics home reference: your guide to understanding genetic conditions.
7. Shadel, GS, & Clayton, DA (1997). Mitochondrial DNA maintenance in vertebrates. Annual review of biochemistry, 66 (1), 409-435.
8. Simmons, MJ, & Snustad, DP (2006). Principles of genetics. John Wiley & Sons.