Generality
Mitochondrial DNA, or mtDNA, is the deoxyribonucleic acid that resides inside the mitochondria, ie the organelles of eukaryotic cells responsible for the very important cellular process of oxidative phosphorylation.
However, it also has some peculiarities, both structural and functional, which make it unique in its kind. These peculiarities include: the circularity of the double strand of nucleotides, the content of genes (which is only 37 elements) and the almost total absence of non-coding nucleotide sequences.
Mitochondrial DNA performs a fundamental function for the survival of cells: it produces the enzymes necessary for the realization of oxidative phosphorylation.
What is mitochondrial DNA?
Mitochondrial DNA, or mtDNA, is the DNA located within the mitochondria.
Mitochondria are those large cellular organelles, typical of eukaryotic organisms, which convert the chemical energy contained in food into ATP, which is a form of energy that can be exploited by cells.
BACKGROUND ON THE STRUCTURE AND FUNCTIONING OF MITOCHONDRONS
Tubular, filamentous or granular in shape, mitochondria reside in the cytoplasm, occupying almost 25% of the volume of the latter.
They have two phospholipid bilayer membranes, one more external and one more internal.
The outermost membrane, known as the outer mitochondrial membrane, represents the perimeter of each mitochondrion and has transport proteins (porins and more), which make it permeable to molecules of a size equal to or less than 5,000 daltons.
The innermost membrane, known as the inner mitochondrial membrane, contains all the enzymatic (or enzymatic) and coenzyme components, necessary for the synthesis of ATP, and defines a central space, called the matrix.
Unlike the outermost membrane, the inner mitochondrial membrane has numerous invaginations - the so-called ridges - which increase its total area.
Between the two mitochondrial membranes, there is a space of nearly 60-80 Angstroms (A). This space is called the intermembrane space. The intermembrane space has a composition very similar to that of the cytoplasm.
The synthesis of ATP, operated by the mitochondria, is a very complex process, which biologists identify with the term oxidative phosphorylation.
PRECISE LOCATION OF MITOCHONDRAL DNA AND QUANTITY
Figure: a human mitochondrion.
Mitochondrial DNA resides in the mitochondrial matrix, that is, in the space delimited by the inner mitochondrial membrane.
According to reliable scientific studies, each mitochondrion can contain from 2 to 12 copies of mitochondrial DNA.
Given the fact that, in the human body, some cells can contain several thousand mitochondria within them, the total number of copies of mitochondrial DNA in a single human cell can reach as much as 20,000 units.
Please note: the number of mitochondria in human cells varies according to the cell type. For example, hepatocytes (i.e. liver cells) can contain between 1,000 and 2,000 mitochondria each, while erythrocytes (i.e. red blood cells) are totally devoid of them.
Structure
The general structure of a mitochondrial DNA molecule resembles the general structure of nuclear DNA, that is, the genetic heritage present within the nucleus of eukaryotic cells.
Indeed, analogously to nuclear DNA:
- Mitochondrial DNA is a biopolymer, consisting of two long strands of nucleotides. Nucleotides are organic molecules, resulting from the union of three elements: a sugar with 5 carbon atoms (in the case of DNA, deoxyribose), a nitrogenous base and a phosphate group.
- Each nucleotide of mitochondrial DNA binds to the next nucleotide of the same strand by means of a phosphodiester bond between the carbon 3 of its deoxyribose and the phosphate group of the immediately following nucleotide.
- The two strands of mitochondrial DNA have opposite orientations, with the end of one interacting with the end of the other and vice versa. This particular arrangement is known as the antiparallel arrangement (or antiparallel orientation).
- The two strands of mitochondrial DNA interact with each other through the nitrogenous bases.
Specifically, each nitrogenous base of each filament establishes hydrogen bonds with one and only one nitrogenous base, present on the other filament.
This type of interaction is called "pairing between nitrogenous bases" or "pair of nitrogenous bases". - The nitrogenous bases of mitochondrial DNA are adenine, thymine, cytosine and guanine.
The pairing to which these nitrogenous bases give rise are not random, but highly specific: adenine interacts only with thymine, while cytosine only interacts with guanine. - Mitochondrial DNA is home to genes (or gene sequences). Genes are sequences of more or less long nucleotides, with a well-defined biological significance. In most cases, they give rise to proteins.
STRUCTURAL PARTICULARITIES OF MITOCHONDRAL DNA
Beyond the aforementioned analogies, human mitochondrial DNA has some structural peculiarities, which distinguish it considerably from human nuclear DNA.
First, it is a circular molecule, while nuclear DNA is a linear molecule.
Thus, it has 16,569 nitrogenous base pairs, while nuclear DNA has a whopping 3.3 billion.
It contains 37 genes, while nuclear DNA appears to contain between 20,000 and 25,000.
It is not organized in chromosomes, while nuclear DNA is divided into 23 chromosomes and forms, with some specific proteins, a substance called chromatin.
Finally, it includes a series of nucleotides that participate in two genes at the same time, while nuclear DNA has genes whose nucleotide sequences are well defined and distinct from each other.
Origin
Mitochondrial DNA most likely has a "bacterial" origin.
In fact, on the basis of numerous independent studies, molecular biologists believe that the cellular presence of mitochondrial DNA is the result of the incorporation, by ancestral eukaryotic cells, of independent bacterial organisms, very similar to mitochondria.
This curious discovery has only partially amazed the scientific community, as the DNA present in bacteria is generally a circular nucleotide strand, like mitochondrial DNA.
The theory according to which mitochondria and mitochondrial DNA have a "bacterial origin takes the name of" endosymbiotic theory ", from the word" endosymbiosis. "Briefly, in biology, the term" endosymbiosis "indicates a collaboration between two organisms, which involves the "incorporation of one within" the other, in order to gain a certain advantage.
Curiosity
According to reliable scientific studies, in the course of evolution many bacterial genes, present on the future mitochondrial DNA, would have changed location, moving into nuclear DNA.
In other words, at the beginning of endosymbiosis, some genes now present on nuclear DNA resided in the DNA of those bacterial organisms, which would later become mitochondria.
To support the theory relating to a shift of genes between mitochondrial DNA and nuclear DNA, is the observation that certain genes derive from mitochondrial DNA, in some species, and from nuclear DNA, in others.
Function
Mitochondrial DNA produces enzymes (ie proteins), necessary for the correct implementation of the delicate oxidative phosphorylation process.
The instructions for synthesizing these enzymes reside in the 37 genes that make up the mitochondrial DNA genome.
WHAT MITOCHONDRAL DNA GENES CODE: THE DETAILS
The 37 genes of the mitochondrial DNA code for: proteins, tRNA and rRNA.
In particular:
- 13 encode 13 proteins responsible for carrying out oxidative phosphorylation
- 22 code for 22 tRNA molecules
- 2 encode 2 rRNA molecules
The molecules of tRNA and rRNA are fundamental to the synthesis of the aforementioned 13 proteins, as they make up the machinery that regulates their production.
So, in other words, mitochondrial DNA possesses the information to produce a certain set of proteins and the tools necessary for their synthesis.
What are RNA, tRNA and rRNA?
RNA, or ribonucleic acid, is the nucleic acid that plays a fundamental role in the generation of proteins, starting from DNA.
Generally single-stranded, the ANN can exist in various forms (or types), depending on the specific function to which it is delegated.
TRNA and rRNA are two of these possible forms.
The tRNA is used to add amino acids during the process of making proteins. Amino acids are the molecular units that make up proteins.
The rRNA forms the ribosomes, that is the cellular structures in which the synthesis of proteins takes place.
To know in detail the ANN and its functions, the readers can click here.
FUNCTIONAL DETAILS OF MITOCHONDRAL DNA
From a functional point of view, mitochondrial DNA has some peculiar characteristics that clearly distinguish it from nuclear DNA.
Here is what these peculiar characteristics consist of:
- Mitochondrial DNA is semi-independent, in the sense that it needs the intervention of some proteins synthesized from nuclear DNA.
On the other hand, nuclear DNA is completely autonomous and produces by itself everything it needs to properly perform its tasks. - Mitochondrial DNA has a slightly different genetic code than nuclear DNA.This leads to a number of differences in the making of proteins: if a certain sequence of nucleotides in nuclear DNA leads to the creation of a certain protein, the same sequence in mitochondrial DNA leads to the formation of a slightly different protein.
- Mitochondrial DNA possesses very few non-coding nucleotide sequences, that is, they do not produce any proteins, tRNAs or rRNAs. In percentage terms, only 3% of mitochondrial DNA is non-coding.
On the other hand, nuclear DNA is only 7% coding, so it contains a lot of non-coding nucleotide sequences (as much as 93%).
Table: summary of the differences between human mitochondrial DNA and human nuclear DNA.
Mitochondrial DNA
Nuclear DNA
- It is circular
- It is linear
- It has 16,569 nitrogenous base pairs in all
- It has a total of 3.3 billion nitrogenous base pairs
- It contains 37 genes in all
- It contains between 20,000 and 25,000 genes
- To function properly it needs the support of some gene products, deriving from nuclear DNA
- It is autonomous and produces by itself everything it needs to properly perform its functions
- It can be present in several copies within each individual mitochondrion
- It is unique, that is, it is in one copy only, and it resides in the core
- 97% of the nucleotide sequence that compose it is coding
- Only 7% of the nucleotide sequence that compose it is coding
- It is not organized into chromosomes
- It is divided into 23 chromosomes
- It uses a genetic code slightly different from the, so to speak, "traditional" one
- Use the "traditional" genetic code
- Its inheritance is maternal
- Its inheritance is half maternal and half paternal
- Some of its nucleotides participate in two genes at the same time
- The sequences of nucleotides that make up the genes are well distinguished from each other
Inheritance
Mitochondrial DNA inheritance is strictly maternal.
This means that, in a pair of parents, it is the woman who transmits the mitochondrial DNA to the progeny (ie to the children).
In a completely opposite way to the above, nuclear DNA inheritance is half maternal and half paternal. In other words, both parents contribute equally to the transmission of nuclear DNA in offspring.
Please note: maternal inheritance of mitochondrial DNA also involves the mitochondrial structure. Hence, the mitochondria present in an individual are maternal.
Associated pathologies
Premise: A genetic mutation is a permanent change in the sequence of nucleotides, which make up a nuclear or mitochondrial DNA gene.
Generally, the presence of a genetic mutation results in an "alteration or loss of normal function of the gene involved.
The presence of mutations in the mitochondrial DNA genes can lead to a wide range of diseases, including:
- Leber's hereditary optic neuropathy
- Kearns-Sayre syndrome
- Leigh's syndrome
- The deficiency of cytochrome C oxidase
- Progressive external ophthalmoplegia
- Pearson's syndrome
- Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS syndrome)
- Diabetes with maternally transmitted deafness
- Myoclonic epilepsy with irregular red fibers
Regarding the pathological conditions linked to one or more mitochondrial DNA mutations, two aspects need to be clarified.
First, the severity of the disease depends on the quantitative relationship between mutated mitochondrial DNAs and healthy, normal mitochondrial DNAs. If the number of mutated mitochondrial DNAs is vastly greater than that of healthy DNAs, the resulting condition will be more severe.
Secondly, mutations in mitochondrial DNA only affect some tissues of the organism, in particular those that require large quantities of ATP resulting from the oxidative phosphorylation process. This is quite understandable: to suffer more than one malfunction of mitochondrial DNA are the cells that most need the function that mitochondrial DNA normally fulfills.
LEBER'S HEREDITARY OPTICAL NEUROPATHY
Leber's hereditary optic neuropathy arises as a result of the mutation of as many as four mitochondrial DNA genes. These genes contain the information that leads to the synthesis of the so-called complex I (or NADH oxide-reductase), one of the various enzymes involved in the oxidative phosphorylation process.
The manifestations of the pathology consist in a progressive degeneration of the optic nerve and a gradual loss of vision.
KEARNS-SAYRE SYNDROME
Kearns-Sayre syndrome appears due to the lack of a fair amount of mitochondrial DNA (N.B: the lack of a certain nucleotide sequence is called a deletion).
People with Kearns-Sayre syndrome develop ophthalmoplegia (total or partial paralysis of the oculomotor muscles), a form of retinopathy and heart rhythm abnormalities (atrioventricular block).
LEIGH'S SYNDROME
Leigh syndrome arises as a result of mitochondrial DNA mutations, which can affect the ATP-synthase protein (also called V-complex) and / or some tRNAs.
Leigh's syndrome is a progressive neurological disease, which appears in infancy or childhood and is responsible for: developmental delay, muscle weakness, peripheral neuropathy, motor disorders, breathing difficulties and ophthalmoplegia.
DEFICITY OF CYTOCHROME C OXIDASE
Cytochrome C oxidase deficiency occurs as a result of the mutation of at least 3 mitochondrial DNA genes. These genes are essential for the correct synthesis of the cytochrome C oxidase (or complex IV) enzyme, involved in the oxidative phosphorylation process.
Typical manifestations of cytochrome C oxidase deficiency consist of: skeletal muscle dysfunction, cardiac dysfunction, renal dysfunction and hepatic dysfunction.
PROGRESSIVE EXTERNAL OPHTHALMOPLEGY
Progressive external ophthalmoplegia arises from the lack of a substantial number of mitochondrial DNA nucleotides (deletion)
With a progressive character (as can be guessed from the name), this pathology causes a paralysis of the oculomotor muscles, with consequent ptosis and considerable visual problems.
PEARSON'S SYNDROME
Pearson's syndrome appears as a result of a conspicuous deletion of mitochondrial DNA, in a way very similar to "progressive external ophthalmoplegia and Kearns-Sayre syndrome.
Typical manifestations of Pearson's syndrome consist of: sideroblastic anemia, pancreatic dysfunction (eg insulin-dependent diabetes), neurological deficits and muscle disorders.
Pearson syndrome usually causes the affected person to die at a young age. In fact, those affected by this pathology rarely reach adulthood.
MELAS SYNDROME
MELAS syndrome, also known as mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes, arises from the mutation of at least 5 mitochondrial DNA genes.
These genes contribute to the synthesis of NADH oxide-reductase, or complex I, and of some tRNAs.
MELAS syndrome involves the presence of neurological disorders, muscle disorders, unusual accumulation of lactic acid in the tissues (with all the accompanying symptoms), breathing problems, loss of bowel function control, recurrent fatigue, kidney problems, heart problems, diabetes , epilepsy and lack of coordination.
OTHER PATHOLOGIES
According to various scientific studies, diseases such as cyclic vomiting syndrome, retinitis pigmentosa, ataxia, Parkinson's disease and Alzheimer's disease, would also see involvement of mitochondrial DNA and some of its mutations.
