Editing Mitochondrial DNA (section)

==Genes on the human mtDNA and their transcription==
{{Further|Human mitochondrial genetics}}
[[File:Human karyotype with bands and sub-bands.png|thumb|Schematic [[karyogram]] showing the [[human genome]], with 23 chromosome pairs as well as the mitochondrial genome (to scale at bottom left, annotated "MT"). Its genome is relatively tiny compared to the rest, and its copy number per human cell varies from 0 ([[erythrocytes]])<ref name="pmid3178814">{{Cite journal |vauthors=Shuster RC, Rubenstein AJ, Wallace DC |date=September 1988 |title=Mitochondrial DNA in anucleate human blood cells |journal=Biochemical and Biophysical Research Communications |volume=155 |issue=3 |pages=1360–1365 |doi=10.1016/s0006-291x(88)81291-9 |pmid=3178814}}</ref> up to 1,500,000 ([[egg cell|oocytes]]).<ref name="pmid28721182">{{Cite journal |vauthors=Zhang D, Keilty D, Zhang ZF, Chian RC |date=March 2017 |title=Mitochondria in oocyte aging: current understanding |journal=Facts, Views & Vision in ObGyn |volume=9 |issue=1 |pages=29–38 |pmc=5506767 |pmid=28721182}}</ref><br />{{further|Karyotype}}]]
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 RNA]]s (12S and 16S), and 14 [[transfer RNA]]s (tRNAs). The light strand encodes one subunit and 8 tRNAs. So, altogether mtDNA encodes for two rRNAs, 22 tRNAs, and 13 [[protein subunit]]s, all of which are involved in the oxidative phosphorylation process.<ref name="pmid29945721">{{Cite journal |vauthors=Barshad G, Marom S, Cohen T, Mishmar D |date=September 2018 |title=Mitochondrial DNA Transcription and Its Regulation: An Evolutionary Perspective |journal=Trends in Genetics |volume=34 |issue=9 |pages=682–692 |doi=10.1016/j.tig.2018.05.009 |pmid=29945721 |s2cid=49430452}}</ref><ref name="pmid31064115">{{Cite journal |vauthors=Barchiesi A, Vascotto C |date=May 2019 |title=Transcription, Processing, and Decay of Mitochondrial RNA in Health and Disease |journal=International Journal of Molecular Sciences |volume=20 |issue=9 |page=2221 |doi=10.3390/ijms20092221 |pmc=6540609 |pmid=31064115 |doi-access=free}}</ref>
* [https://www.ncbi.nlm.nih.gov/nuccore/NC_012920.1?report=graph The complete sequence of the human mitochondrial DNA in graphic form]

{| class="wikitable sortable" style="text-align: center;"
|+ The 37 genes of the [[Cambridge Reference Sequence]] for human mitochondrial DNA and their locations<ref name="NCBI NC_012920">''Homo sapiens'' mitochondrion, complete genome. [https://www.ncbi.nlm.nih.gov/nuccore/NC_012920.1 "Revised Cambridge Reference Sequence (rCRS): accession NC_012920"] {{Webarchive|url=https://web.archive.org/web/20200406083231/https://www.ncbi.nlm.nih.gov/nuccore/NC_012920.1 |date=6 April 2020 }}, ''[[National Center for Biotechnology Information]]''. Retrieved on 20 February 2017.</ref>
! Gene
! Type
! Product
! Positions <br />in the mitogenome
! Strand
|-
| [[MT-ATP8]]
| [[protein-coding gene|protein coding]]
| [[ATP synthase]], Fo subunit 8 (complex V)
| 08,366–08,572 (overlap with MT-ATP6)
| H
|-
| [[MT-ATP6]]
| protein coding
| [[ATP synthase]], Fo subunit 6 (complex V)
| 08,527–09,207 (overlap with MT-ATP8)
| H
|-
| [[MT-CO1]]
| protein coding
| [[Cytochrome c oxidase]], subunit 1 (complex IV)
| 05,904–07,445
| H
|-
| [[MT-CO2]]
| protein coding
| [[Cytochrome c oxidase]], subunit 2 (complex IV)
| 07,586–08,269
| H
|-
| [[MT-CO3]]
| protein coding
| [[Cytochrome c oxidase]], subunit 3 (complex IV)
| 09,207–09,990
| H
|-
| [[MT-CYB]]
| protein coding
| [[Cytochrome b]] (complex III)
| 14,747–15,887
| H
|-
| [[MT-ND1]]
| protein coding
| [[NADH dehydrogenase]], subunit 1 (complex I)
| 03,307–04,262
| H
|-
| [[MT-ND2]]
| protein coding
| [[NADH dehydrogenase]], subunit 2 (complex I)
| 04,470–05,511
| H
|-
| [[MT-ND3]]
| protein coding
| [[NADH dehydrogenase]], subunit 3 (complex I)
| 10,059–10,404
| H
|-
| [[MT-ND4L]]
| protein coding
| [[NADH dehydrogenase]], subunit 4L (complex I)
| 10,470–10,766 (overlap with MT-ND4)
| H
|-
| [[MT-ND4]]
| protein coding
| [[NADH dehydrogenase]], subunit 4 (complex I)
| 10,760–12,137 (overlap with MT-ND4L)
| H
|-
| [[MT-ND5]]
| protein coding
| [[NADH dehydrogenase]], subunit 5 (complex I)
| 12,337–14,148
| H
|-
| [[MT-ND6]]
| protein coding
| [[NADH dehydrogenase]], subunit 6 (complex I)
| 14,149–14,673
| L
|-
| [[MT-RNR2]]
| protein coding
| [[Humanin]]
| —
| —
|-
| [[MT-TA]]
| transfer RNA
| tRNA-[[Alanine]] (Ala or A)
| 05,587–05,655
| L
|- align=center
| [[MT-TR]]
| transfer RNA
| tRNA-[[Arginine]] (Arg or R)
| 10,405–10,469
| H
|- align=center
| [[MT-TN]]
| transfer RNA
| tRNA-[[Asparagine]] (Asn or N)
| 05,657–05,729
| L
|- align=center
| [[MT-TD]]
| transfer RNA
| tRNA-[[Aspartic acid]] (Asp or D)
| 07,518–07,585
| H
|- align=center
| [[MT-TC]]
| transfer RNA
| tRNA-[[Cysteine]] (Cys or C)
| 05,761–05,826
| L
|- align=center
| [[MT-TE]]
| transfer RNA
| tRNA-[[Glutamic acid]] (Glu or E)
| 14,674–14,742
| L
|- align=center
| [[MT-TQ]]
| transfer RNA
| tRNA-[[Glutamine]] (Gln or Q)
| 04,329–04,400
| L
|- align=center
| [[MT-TG]]
| transfer RNA
| tRNA-[[Glycine]] (Gly or G)
| 09,991–10,058
| H
|- align=center
| [[MT-TH]]
| transfer RNA
| tRNA-[[Histidine]] (His or H)
| 12,138–12,206
| H
|- align=center
| [[MT-TI]]
| transfer RNA
| tRNA-[[Isoleucine]] (Ile or I)
| 04,263–04,331
| H
|- align=center
| [[MT-TL1]]
| transfer RNA
| tRNA-[[Leucine]] (Leu-UUR or L)
| 03,230–03,304
| H
|- align=center
| [[MT-TL2]]
| transfer RNA
| tRNA-[[Leucine]] (Leu-CUN or L)
| 12,266–12,336
| H
|- align=center
| [[MT-TK]]
| transfer RNA
| tRNA-[[Lysine]] (Lys or K)
| 08,295–08,364
| H
|- align=center
| [[MT-TM]]
| transfer RNA
| tRNA-[[Methionine]] (Met or M)
| 04,402–04,469
| H
|- align=center
| [[MT-TF]]
| transfer RNA
| tRNA-[[Phenylalanine]] (Phe or F)
| 00,577–00,647
| H
|- align=center
| [[MT-TP]]
| transfer RNA
| tRNA-[[Proline]] (Pro or P)
| 15,956–16,023
| L
|- align=center
| [[MT-TS1]]
| transfer RNA
| tRNA-[[Serine]] (Ser-UCN or S)
| 07,446–07,514
| L
|- align=center
| [[MT-TS2]]
| transfer RNA
| tRNA-[[Serine]] (Ser-AGY or S)
| 12,207–12,265
| H
|- align=center
| [[MT-TT]]
| transfer RNA
| tRNA-[[Threonine]] (Thr or T)
| 15,888–15,953
| H
|- align=center
| [[MT-TW]]
| transfer RNA
| tRNA-[[Tryptophan]] (Trp or W)
| 05,512–05,579
| H
|- align=center
| [[MT-TY]]
| transfer RNA
| tRNA-[[Tyrosine]] (Tyr or Y)
| 05,826–05,891
| L
|- align=center
| [[MT-TV (mitochondrial)|MT-TV]]
| transfer RNA
| tRNA-[[Valine]] (Val or V)
| 01,602–01,670
| H
|-
| [[MT-RNR1]]
| ribosomal RNA
| Small subunit: SSU (12S)
| 00,648–01,601
| H
|-
| [[MT-RNR2]]
| ribosomal RNA
| Large subunit: LSU (16S)
| 01,671–03,229
| H
|}

Between most (but not all) protein-coding regions, tRNAs are present (see the [[#Map of the human mitochondrial genome|human mitochondrial genome map]]). 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.<ref>{{Cite journal |vauthors=Falkenberg M, Larsson NG, Gustafsson CM |date=2007-06-19 |title=DNA replication and transcription in mammalian mitochondria |journal=Annual Review of Biochemistry |volume=76 |issue=1 |pages=679–699 |doi=10.1146/annurev.biochem.76.060305.152028 |pmid=17408359}}</ref> Folded tRNAs therefore act as secondary structure punctuations.<ref>{{Cite journal |vauthors=Ojala D, Montoya J, Attardi G |date=April 1981 |title=tRNA punctuation model of RNA processing in human mitochondria |journal=Nature |volume=290 |issue=5806 |pages=470–474 |bibcode=1981Natur.290..470O |doi=10.1038/290470a0 |pmid=7219536 |s2cid=4323371}}</ref>

Transcription is done by the single-subunit mitochondrial RNA polymerase (POLRMT). In association with two of accessory factors, mitochondrial transcription factor A (TFAM) and mitochondrial transcription factor B2 (TFB2M), the POLRMT complex recognizes promoters and initiates transcription.<ref>{{Cite journal |last1=Falkenberg |first1=Maria |last2=Gaspari |first2=Martina |last3=Rantanen |first3=Anja |last4=Trifunovic |first4=Aleksandra |last5=Larsson |first5=Nils-Göran |last6=Gustafsson |first6=Claes M. |date=July 2002 |title=Mitochondrial transcription factors B1 and B2 activate transcription of human mtDNA |url=https://www.nature.com/articles/ng909z |journal=Nature Genetics |language=en |volume=31 |issue=3 |pages=289–294 |doi=10.1038/ng909 |pmid=12068295 |issn=1546-1718}}</ref> Transcription resulted in polycistronic transcripts that are processed in discrete mitochondrial RNA granules into individual mRNAs, tRNAs, and rRNAs.<ref>{{Cite journal |last1=Falkenberg |first1=Maria |last2=Larsson |first2=Nils-Göran |last3=Gustafsson |first3=Claes M. |date=2024 |title=Replication and Transcription of Human Mitochondrial DNA |journal=Annual Review of Biochemistry |language=en |volume=93 |issue=1 |pages=47–77 |doi=10.1146/annurev-biochem-052621-092014 |doi-access=free |pmid=38594940 |issn=0066-4154}}</ref>

===Regulation of transcription===

The promoters for the initiation of the transcription of the heavy and light strands are located in the main non-coding region of the mtDNA called the displacement loop, the [[D-loop]].<ref name="pmid29945721" /> There is evidence that the transcription of the mitochondrial rRNAs is regulated by the heavy-strand promoter 1 (HSP1), and the transcription of the polycistronic transcripts coding for the protein subunits are regulated by HSP2.<ref name="pmid29945721" />

Measurement of the levels of the mtDNA-encoded RNAs in bovine tissues has shown that there are major differences in the expression of the mitochondrial RNAs relative to total tissue RNA.<ref name="1993-Raikhinstein">{{Cite journal |vauthors=Raikhinstein M, Hanukoglu I |date=November 1993 |title=Mitochondrial-genome-encoded RNAs: differential regulation by corticotropin in bovine adrenocortical cells |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=90 |issue=22 |pages=10509–10513 |bibcode=1993PNAS...9010509R |doi=10.1073/pnas.90.22.10509 |pmc=47806 |pmid=7504267 |doi-access=free}}</ref> Among the 12 tissues examined the highest level of expression was observed in the heart, followed by brain and steroidogenic tissue samples.<ref name="1993-Raikhinstein" />

As demonstrated by the effect of the trophic hormone [[ACTH]] on adrenal cortex cells, the expression of the mitochondrial genes may be strongly regulated by external factors, apparently to enhance the synthesis of mitochondrial proteins necessary for energy production.<ref name="1993-Raikhinstein" /> Interestingly, while the expression of protein-encoding genes was stimulated by ACTH, the levels of the mitochondrial 16S rRNA showed no significant change.<ref name="1993-Raikhinstein" />