Mitochondrial DNA

Mitochondrial DNA is the DNA located in the mitochondria organelles in a eukaryotic cell that converts chemical energy from food into adenosine triphosphate. Mitochondrial DNA is a small portion of the DNA contained in a eukaryotic cell; most of the DNA is in the cell nucleus, and, in plants and algae, the DNA also is found in plastids, such as chloroplasts. Mitochondrial DNA is responsible for coding of 13 essential subunits of the complex oxidative phosphorylation system which has a role in cellular energy conversion.
Human mitochondrial DNA was the first significant part of the human genome to be sequenced. This sequencing revealed that human mtDNA has 16,569 base pairs and encodes 13 proteins. As in other vertebrates, the human mitochondrial genetic code differs slightly from nuclear DNA.
Since animal mtDNA evolves faster than nuclear genetic markers, it represents a mainstay of phylogenetics and evolutionary biology. It also permits tracing the relationships of populations, and so has become important in anthropology and biogeography.

Origin

Nuclear and mitochondrial DNA are thought to have separate evolutionary origins, with the mtDNA derived from the circular genomes of bacteria engulfed by the ancestors of modern eukaryotic cells. This theory is called the endosymbiotic theory. In the cells of extant organisms, the vast majority of the proteins in the mitochondria are coded by nuclear DNA, but the genes for some, if not most, of them are thought to be of bacterial origin, having been transferred to the eukaryotic nucleus during evolution.
The reasons mitochondria have retained some genes are debated. The existence in some species of mitochondrion-derived organelles lacking a genome suggests that complete gene loss is possible, and transferring mitochondrial genes to the nucleus has several advantages. The difficulty of targeting remotely produced hydrophobic protein products to the mitochondrion is one hypothesis for why some genes are retained in mtDNA; colocalisation for redox regulation is another, citing the desirability of localised control over mitochondrial machinery. Recent analysis of a wide range of mtDNA genomes suggests that both these features may dictate mitochondrial gene retention.

Genome structure and diversity

Across all organisms, there are six main mitochondrial genome types, classified by structure, size, presence of introns or plasmid like structures, and whether the genetic material is a singular molecule or collection of homogeneous or heterogeneous molecules.
In many unicellular organisms, and in rare cases also in multicellular organisms, the mtDNA is linear DNA. Most of these linear mtDNAs possess telomerase-independent telomeres with different modes of replication, which have made them interesting objects of research because many of these unicellular organisms with linear mtDNA are known pathogens.

Animals

Most animals have a circular mitochondrial genome. Medusozoa and calcarea clades however include species with linear mitochondrial chromosomes. With a few exceptions, animals have 37 genes in their mitochondrial DNA: 13 for proteins, 22 for tRNAs, and 2 for rRNAs.
Mitochondrial genomes for animals average about 16,000 base pairs in length. The anemone Isarachnanthus nocturnus has the largest mitochondrial genome of any animal at 80,923 bp. The smallest known mitochondrial genome in animals belongs to the comb jelly Vallicula multiformis, which consist of 9,961 bp.
In February 2020, a jellyfish-related parasite – Henneguya salminicola – was discovered that lacks a mitochondrial genome but retains structures deemed mitochondrion-related organelles. Moreover, nuclear DNA genes involved in aerobic respiration and mitochondrial DNA replication and transcription were either absent or present only as pseudogenes. This is the first multicellular organism known to have this absence of aerobic respiration and live completely free of oxygen dependency.

Plants and fungi

There are three different mitochondrial genome types in plants and fungi. The first type is a circular genome that has introns and may range from 19 to 1000 kbp in length. The second genome type is a circular genome that also has a plasmid-like structure . The final genome type found in plants and fungi is a linear genome made up of homogeneous DNA molecules.
Great variation in mtDNA gene content and size exists among fungi and plants, although there appears to be a core subset of genes present in all eukaryotes. In Fungi, however, there is no single gene shared among all mitogenomes.
Some plant species have enormous mitochondrial genomes, with Silene conica mtDNA containing as many as 11,300,000 base pairs. Surprisingly, even those huge mtDNAs contain the same number and kinds of genes as related plants with much smaller mtDNAs.
The genome of the mitochondrion of the cucumber consists of three circular chromosomes, which are entirely or largely autonomous with regard to their replication.

Protists

s contain the most diverse mitochondrial genomes, with five different types found in this kingdom. Type 2, type 3, and type 5 of the plant and fungal genomes also exist in some protists, as do two unique genome types. One of these unique types is a heterogeneous collection of circular DNA molecules while the other is a heterogeneous collection of linear molecules. Genome types 4 and 6 each range from 1–200 kbp in size.
The smallest mitochondrial genome sequenced to date is the 5,967 bp mtDNA of the parasite Plasmodium falciparum.
Endosymbiotic gene transfer, the process by which genes that were coded in the mitochondrial genome are transferred to the cell's main genome, likely explains why more complex organisms such as humans have smaller mitochondrial genomes than simpler organisms such as protists.

Genome type	Traditional kingdom	Introns	Size	Shape	Description
1	Animal	No	11–28 kbp	Circular	Single molecule
2	Fungi, Plant, Protista	Yes	19–1000 kbp	Circular	Single molecule
3	Fungi, Plant, Protista	No	20–1000 kbp	Circular	Large molecule and small plasmid-like structures
4	Protista	No	1–200 kbp	Circular	Heterogeneous group of molecules
5	Fungi, Plant, Protista	No	1–200 kbp	Linear	Homogeneous group of molecules
6	Protista	No	1–200 kbp	Linear	Heterogeneous group of molecules

Replication

The two strands of the human mitochondrial DNA are distinguished as the heavy strand and the light strand. The regulation of mitochondrial DNA replication and transcription initiation is located in a single intergenic noncoding region. In human, the 1,100 base pairs NCR region contains three promoters of two L-strand promoters and one H-strand promoter. Unlike bidirectional and specific origin initiation of nuclear DNA replication, mitochondrial DNA has two strand-specific, unidirectional origins of replication of the leading H strand which located in NCR and the lagging L strand which located in the tRNA gene cluster.
Mitochondrial DNA is replicated by the DNA polymerase gamma complex which is composed of a 140 kDa catalytic DNA polymerase encoded by the POLG gene and two 55 kDa accessory subunits encoded by the POLG2 gene. The replisome machinery is formed by DNA polymerase, TWINKLE and mitochondrial SSB proteins. TWINKLE is a helicase, which unwinds short stretches of dsDNA in the 5' to 3' direction. Mitochondrial single-stranded DNA binding protein coordinates its activity with the POLG during DNA replication. All these polypeptides are encoded in the nuclear genome.
During embryogenesis, replication of mtDNA is strictly down-regulated from the fertilized oocyte through the preimplantation embryo. The resulting reduction in per-cell copy number of mtDNA plays a role in the mitochondrial bottleneck, exploiting cell-to-cell variability to ameliorate the inheritance of damaging mutations. According to Justin St. John and colleagues, "At the blastocyst stage, the onset of mtDNA replication is specific to the cells of the trophectoderm. In contrast, the cells of the inner cell mass restrict mtDNA replication until they receive the signals to differentiate to specific cell types."

DNA repair

Although several DNA repair pathways have been reported to occur in the mitochondria, currently the base excision repair pathway is the pathway most comprehensively described. Proteins that are employed in the maintenance of mitochondrial DNA are encoded by nuclear genes and translocated to the mitochondria. The mitochondria of human cells are capable of repairing DNA base pair mismatches by a pathway that is distinct from the DNA mismatch repair pathway of the nucleus. This distinct mitochondrial pathway includes the activity of the Y box binding protein 1, that likely acts in the mismatch binding and recognition steps of mismatch repair. DNA repair mechanisms specific to the mitochondria may reflect the proximity of the mitochondrial DNA to the oxidative phosphorylation system and consequently to the DNA-damaging reactive oxygen species formed during ATP production.

Genes on the human mtDNA and their transcription

The two strands of the human mitochondrial DNA are distinguished as the heavy strand and the light strand. The heavy strand is rich in guanine and encodes 12 subunits of the oxidative phosphorylation system, two ribosomal RNAs, and 14 transfer RNAs. The light strand encodes one subunit and 8 tRNAs. So, altogether mtDNA encodes for two rRNAs, 22 tRNAs, and 13 protein subunits, all of which are involved in the oxidative phosphorylation process.

Gene	Type	Product	Positions in the mitogenome	Strand
MT-ATP8	protein coding	ATP synthase, Fo subunit 8	08,366–08,572	H
MT-ATP6	protein coding	ATP synthase, Fo subunit 6	08,527–09,207	H
MT-CO1	protein coding	Cytochrome c oxidase, subunit 1	05,904–07,445	H
MT-CO2	protein coding	Cytochrome c oxidase, subunit 2	07,586–08,269	H
MT-CO3	protein coding	Cytochrome c oxidase, subunit 3	09,207–09,990	H
MT-CYB	protein coding	Cytochrome b	14,747–15,887	H
MT-ND1	protein coding	NADH dehydrogenase, subunit 1	03,307–04,262	H
MT-ND2	protein coding	NADH dehydrogenase, subunit 2	04,470–05,511	H
MT-ND3	protein coding	NADH dehydrogenase, subunit 3	10,059–10,404	H
MT-ND4L	protein coding	NADH dehydrogenase, subunit 4L	10,470–10,766	H
MT-ND4	protein coding	NADH dehydrogenase, subunit 4	10,760–12,137	H
MT-ND5	protein coding	NADH dehydrogenase, subunit 5	12,337–14,148	H
MT-ND6	protein coding	NADH dehydrogenase, subunit 6	14,149–14,673	L
MT-RNR2	protein coding	Humanin	—	—
MT-TA	transfer RNA	tRNA-Alanine	05,587–05,655	L
MT-TR	transfer RNA	tRNA-Arginine	10,405–10,469	H
MT-TN	transfer RNA	tRNA-Asparagine	05,657–05,729	L
MT-TD	transfer RNA	tRNA-Aspartic acid	07,518–07,585	H
MT-TC	transfer RNA	tRNA-Cysteine	05,761–05,826	L
MT-TE	transfer RNA	tRNA-Glutamic acid	14,674–14,742	L
MT-TQ	transfer RNA	tRNA-Glutamine	04,329–04,400	L
MT-TG	transfer RNA	tRNA-Glycine	09,991–10,058	H
MT-TH	transfer RNA	tRNA-Histidine	12,138–12,206	H
MT-TI	transfer RNA	tRNA-Isoleucine	04,263–04,331	H
MT-TL1	transfer RNA	tRNA-Leucine	03,230–03,304	H
MT-TL2	transfer RNA	tRNA-Leucine	12,266–12,336	H
MT-TK	transfer RNA	tRNA-Lysine	08,295–08,364	H
MT-TM	transfer RNA	tRNA-Methionine	04,402–04,469	H
MT-TF	transfer RNA	tRNA-Phenylalanine	00,577–00,647	H
MT-TP	transfer RNA	tRNA-Proline	15,956–16,023	L
MT-TS1	transfer RNA	tRNA-Serine	07,446–07,514	L
MT-TS2	transfer RNA	tRNA-Serine	12,207–12,265	H
MT-TT	transfer RNA	tRNA-Threonine	15,888–15,953	H
MT-TW	transfer RNA	tRNA-Tryptophan	05,512–05,579	H
MT-TY	transfer RNA	tRNA-Tyrosine	05,826–05,891	L
MT-TV	transfer RNA	tRNA-Valine	01,602–01,670	H
MT-RNR1	ribosomal RNA	Small subunit: SSU	00,648–01,601	H
MT-RNR2	ribosomal RNA	Large subunit: LSU	01,671–03,229	H

Between most protein-coding regions, tRNAs are present. During transcription, the tRNAs acquire their characteristic L-shape that gets recognized and cleaved by specific enzymes. With the mitochondrial RNA processing, individual mRNA, rRNA, and tRNA sequences are released from the primary transcript. Folded tRNAs therefore act as secondary structure punctuations.
Transcription is done by the single-subunit mitochondrial RNA polymerase. In association with two of accessory factors, mitochondrial transcription factor A and mitochondrial transcription factor B2, the POLRMT complex recognizes promoters and initiates transcription. Transcription resulted in polycistronic transcripts that are processed in discrete mitochondrial RNA granules into individual mRNAs, tRNAs, and rRNAs.