Mitochondrial Biology. Replication-transcription Switch in Human Mitochondria

Overview

Journal Science

Specialty Science

Date 2015 Jan 31

PMID 25635099

Citations 100

Authors

Karen Agaronyan

Yaroslav I Morozov

Michael Anikin

Dmitry Temiakov

Affiliations

Soon will be listed here.

Abstract

Coordinated replication and expression of the mitochondrial genome is critical for metabolically active cells during various stages of development. However, it is not known whether replication and transcription can occur simultaneously without interfering with each other and whether mitochondrial DNA copy number can be regulated by the transcription machinery. We found that interaction of human transcription elongation factor TEFM with mitochondrial RNA polymerase and nascent transcript prevents the generation of replication primers and increases transcription processivity and thereby serves as a molecular switch between replication and transcription, which appear to be mutually exclusive processes in mitochondria. TEFM may allow mitochondria to increase transcription rates and, as a consequence, respiration and adenosine triphosphate production without the need to replicate mitochondrial DNA, as has been observed during spermatogenesis and the early stages of embryogenesis.

Citing Articles

Disruption of mitochondrial DNA integrity in cardiomyocyte injury upon ischemia/reperfusion.

Hu S, Tang X, Zhu F, Liang C, Wang S, Wang H Genes Dis. 2025; 12(3):101282.

PMID: 40028034 PMC: 11870174. DOI: 10.1016/j.gendis.2024.101282.

TEFM facilitates transition from RNA synthesis to DNA synthesis at H-strand replication origin of mtDNA.

Matsuda S, Nakayama M, Do Y, Ishiuchi T, Yagi M, Wanrooij S Commun Biol. 2025; 8(1):202.

PMID: 39922921 PMC: 11807126. DOI: 10.1038/s42003-025-07645-4.

TEFM facilitates uterine corpus endometrial carcinoma progression by activating ROS-NFκB pathway.

Lei J, Zhu Q, Guo J, Chen J, Qi L, Cui M J Transl Med. 2024; 22(1):1151.

PMID: 39731053 PMC: 11673371. DOI: 10.1186/s12967-024-05833-0.

Evolution and maintenance of mtDNA gene content across eukaryotes.

Veeraragavan S, Johansen M, Johnston I Biochem J. 2024; 481(15):1015-1042.

PMID: 39101615 PMC: 11346449. DOI: 10.1042/BCJ20230415.

Identification of TEFM as a potential therapeutic target for LUAD treatment.

Hu W, Yang J, Hu K, Luo G, Chen Z, Lu Z J Transl Med. 2024; 22(1):692.

PMID: 39075464 PMC: 11288054. DOI: 10.1186/s12967-024-05483-2.

References

Wai T, Ao A, Zhang X, Cyr D, Dufort D, Shoubridge E . The role of mitochondrial DNA copy number in mammalian fertility. Biol Reprod. 2010; 83(1):52-62. PMC: 2888963. DOI: 10.1095/biolreprod.109.080887. View

Wanrooij P, Uhler J, Simonsson T, Falkenberg M, Gustafsson C . G-quadruplex structures in RNA stimulate mitochondrial transcription termination and primer formation. Proc Natl Acad Sci U S A. 2010; 107(37):16072-7. PMC: 2941323. DOI: 10.1073/pnas.1006026107. View

Pomerantz R, ODonnell M . What happens when replication and transcription complexes collide?. Cell Cycle. 2010; 9(13):2537-43. PMC: 3918965. DOI: 10.4161/cc.9.13.12122. View

Minczuk M, He J, Duch A, Ettema T, Chlebowski A, Dzionek K . TEFM (c17orf42) is necessary for transcription of human mtDNA. Nucleic Acids Res. 2011; 39(10):4284-99. PMC: 3105396. DOI: 10.1093/nar/gkq1224. View

Van Blerkom J . Mitochondrial function in the human oocyte and embryo and their role in developmental competence. Mitochondrion. 2010; 11(5):797-813. DOI: 10.1016/j.mito.2010.09.012. View

Carling P, Cree L, Chinnery P . The implications of mitochondrial DNA copy number regulation during embryogenesis. Mitochondrion. 2011; 11(5):686-92. DOI: 10.1016/j.mito.2011.05.004. View

Wanrooij P, Uhler J, Shi Y, Westerlund F, Falkenberg M, Gustafsson C . A hybrid G-quadruplex structure formed between RNA and DNA explains the extraordinary stability of the mitochondrial R-loop. Nucleic Acids Res. 2012; 40(20):10334-44. PMC: 3488243. DOI: 10.1093/nar/gks802. View

Monnot S, Samuels D, Hesters L, Frydman N, Gigarel N, Burlet P . Mutation dependance of the mitochondrial DNA copy number in the first stages of human embryogenesis. Hum Mol Genet. 2013; 22(9):1867-72. DOI: 10.1093/hmg/ddt040. View

Schwinghammer K, Cheung A, Morozov Y, Agaronyan K, Temiakov D, Cramer P . Structure of human mitochondrial RNA polymerase elongation complex. Nat Struct Mol Biol. 2013; 20(11):1298-303. PMC: 4321815. DOI: 10.1038/nsmb.2683. View

10.

Morozov Y, Agaronyan K, Cheung A, Anikin M, Cramer P, Temiakov D . A novel intermediate in transcription initiation by human mitochondrial RNA polymerase. Nucleic Acids Res. 2014; 42(6):3884-93. PMC: 3973326. DOI: 10.1093/nar/gkt1356. View

11.

Hallberg B, Larsson N . Making proteins in the powerhouse. Cell Metab. 2014; 20(2):226-40. DOI: 10.1016/j.cmet.2014.07.001. View

12.

Gusarov I, Nudler E . Control of intrinsic transcription termination by N and NusA: the basic mechanisms. Cell. 2001; 107(4):437-49. DOI: 10.1016/s0092-8674(01)00582-7. View

13.

Tahirov T, Temiakov D, Anikin M, Patlan V, McAllister W, Vassylyev D . Structure of a T7 RNA polymerase elongation complex at 2.9 A resolution. Nature. 2002; 420(6911):43-50. DOI: 10.1038/nature01129. View

14.

Ekstrand M, Falkenberg M, Rantanen A, Park C, Gaspari M, Hultenby K . Mitochondrial transcription factor A regulates mtDNA copy number in mammals. Hum Mol Genet. 2004; 13(9):935-44. DOI: 10.1093/hmg/ddh109. View

15.

Clayton D . Replication of animal mitochondrial DNA. Cell. 1982; 28(4):693-705. DOI: 10.1016/0092-8674(82)90049-6. View

16.

Chang D, Clayton D . Priming of human mitochondrial DNA replication occurs at the light-strand promoter. Proc Natl Acad Sci U S A. 1985; 82(2):351-5. PMC: 397036. DOI: 10.1073/pnas.82.2.351. View

17.

Kang D, Miyako K, Kai Y, Irie T, Takeshige K . In vivo determination of replication origins of human mitochondrial DNA by ligation-mediated polymerase chain reaction. J Biol Chem. 1997; 272(24):15275-9. DOI: 10.1074/jbc.272.24.15275. View

18.

Andrews R, Kubacka I, Chinnery P, Lightowlers R, Turnbull D, Howell N . Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA. Nat Genet. 1999; 23(2):147. DOI: 10.1038/13779. View

19.

Thundathil J, Filion F, Smith L . Molecular control of mitochondrial function in preimplantation mouse embryos. Mol Reprod Dev. 2005; 71(4):405-13. DOI: 10.1002/mrd.20260. View

20.

Wallace D . A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu Rev Genet. 2005; 39:359-407. PMC: 2821041. DOI: 10.1146/annurev.genet.39.110304.095751. View