Rearrangements of Human Mitochondrial DNA (mtDNA): New Insights into the Regulation of MtDNA Copy Number and Gene Expression

Overview

Journal Mol Biol Cell

Specialties Cell Biology
Molecular Biology

Date 2000 Apr 6

PMID 10749943

Citations 35

Authors

Y Tang

E A Schon

E Wilichowski

E Davidson

M P King

Affiliations

Soon will be listed here.

Abstract

Mitochondria from patients with Kearns-Sayre syndrome harboring large-scale rearrangements of human mitochondrial DNA (mtDNA; both partial deletions and a partial duplication) were introduced into human cells lacking endogenous mtDNA. Cytoplasmic hybrids containing 100% wild-type mtDNA, 100% mtDNA with partial duplications, and 100% mtDNA with partial deletions were isolated and characterized. The cell lines with 100% deleted mtDNAs exhibited a complete impairment of respiratory chain function and oxidative phosphorylation. In contrast, there were no detectable respiratory chain or protein synthesis defects in the cell lines with 100% duplicated mtDNAs. Unexpectedly, the mass of mtDNA was identical in all cell lines, despite the fact that different lines contained mtDNAs of vastly different sizes and with different numbers of replication origins, suggesting that mtDNA copy number may be regulated by tightly controlled mitochondrial dNTP pools. In addition, quantitation of mtDNA-encoded RNAs and polypeptides in these lines provided evidence that mtDNA gene copy number affects gene expression, which, in turn, is regulated at both the post-transcriptional and translational levels.

Citing Articles

Mechanisms and pathologies of human mitochondrial DNA replication and deletion formation.

Bernardino Gomes T, Vincent A, Menger K, Stewart J, Nicholls T Biochem J. 2024; 481(11):683-715.

PMID: 38804971 PMC: 11346376. DOI: 10.1042/BCJ20230262.

Cellular and Molecular Responses to Mitochondrial DNA Deletions in Kearns-Sayre Syndrome: Some Underlying Mechanisms.

Yazdani M Mol Neurobiol. 2024; 61(8):5665-5679.

PMID: 38224444 DOI: 10.1007/s12035-024-03938-7.

Insights regarding mitochondrial DNA copy number alterations in human cancer (Review).

Abd Radzak S, Mohd Khair S, Ahmad F, Patar A, Idris Z, Yusoff A Int J Mol Med. 2022; 50(2).

PMID: 35713211 PMC: 9304817. DOI: 10.3892/ijmm.2022.5160.

Genome-wide analysis of mitochondrial DNA copy number reveals loci implicated in nucleotide metabolism, platelet activation, and megakaryocyte proliferation.

Longchamps R, Yang S, Castellani C, Shi W, Lane J, Grove M Hum Genet. 2021; 141(1):127-146.

PMID: 34859289 PMC: 8758627. DOI: 10.1007/s00439-021-02394-w.

Mitochondrial DNA: cellular genotoxic stress sentinel.

Wu Z, Sainz A, Shadel G Trends Biochem Sci. 2021; 46(10):812-821.

PMID: 34088564 PMC: 9809014. DOI: 10.1016/j.tibs.2021.05.004.

References

Murdock D, Boone B, Esposito L, Wallace D . Up-regulation of nuclear and mitochondrial genes in the skeletal muscle of mice lacking the heart/muscle isoform of the adenine nucleotide translocator. J Biol Chem. 1999; 274(20):14429-33. DOI: 10.1074/jbc.274.20.14429. View

Nakase H, Moraes C, Rizzuto R, Lombes A, DiMauro S, Schon E . Transcription and translation of deleted mitochondrial genomes in Kearns-Sayre syndrome: implications for pathogenesis. Am J Hum Genet. 1990; 46(3):418-27. PMC: 1683616. View

Enriquez J, Fernandez-Silva P, Montoya J . Autonomous regulation in mammalian mitochondrial DNA transcription. Biol Chem. 1999; 380(7-8):737-47. DOI: 10.1515/BC.1999.094. View

Rotig A, Bessis J, Romero N, Cormier V, Saudubray J, Narcy P . Maternally inherited duplication of the mitochondrial genome in a syndrome of proximal tubulopathy, diabetes mellitus, and cerebellar ataxia. Am J Hum Genet. 1992; 50(2):364-70. PMC: 1682469. View

Anderson S, Bankier A, Barrell B, de Bruijn M, Coulson A, Drouin J . Sequence and organization of the human mitochondrial genome. Nature. 1981; 290(5806):457-65. DOI: 10.1038/290457a0. View

Larsson N, Oldfors A, Holme E, Clayton D . Low levels of mitochondrial transcription factor A in mitochondrial DNA depletion. Biochem Biophys Res Commun. 1994; 200(3):1374-81. DOI: 10.1006/bbrc.1994.1603. View

Zhao X, Muller E, Rothstein R . A suppressor of two essential checkpoint genes identifies a novel protein that negatively affects dNTP pools. Mol Cell. 1998; 2(3):329-40. DOI: 10.1016/s1097-2765(00)80277-4. View

Mertz L, Rashtchian A . Nucleotide imbalance and polymerase chain reaction: effects on DNA amplification and synthesis of high specific activity radiolabeled DNA probes. Anal Biochem. 1994; 221(1):160-5. DOI: 10.1006/abio.1994.1392. View

Nagley P, Linnane A . Biogenesis of mitochondria. XXI. Studies on the nature of the mitochondrial genome in yeast: the degenerative effects of ethidium bromide on mitochondrial genetic information in a respiratory competent strain. J Mol Biol. 1972; 66(1):181-93. DOI: 10.1016/s0022-2836(72)80015-9. View

10.

Lecrenier N, Foury F . Overexpression of the RNR1 gene rescues Saccharomyces cerevisiae mutants in the mitochondrial DNA polymerase-encoding MIP1 gene. Mol Gen Genet. 1995; 249(1):1-7. DOI: 10.1007/BF00290229. View

11.

Sciacco M, Bonilla E, Schon E, DiMauro S, Moraes C . Distribution of wild-type and common deletion forms of mtDNA in normal and respiration-deficient muscle fibers from patients with mitochondrial myopathy. Hum Mol Genet. 1994; 3(1):13-9. DOI: 10.1093/hmg/3.1.13. View

12.

Schultz R, Swoap S, McDaniel L, Zhang B, Koon E, Garry D . Differential expression of mitochondrial DNA replication factors in mammalian tissues. J Biol Chem. 1998; 273(6):3447-51. DOI: 10.1074/jbc.273.6.3447. View

13.

Nishino I, Spinazzola A, Hirano M . Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder. Science. 1999; 283(5402):689-92. DOI: 10.1126/science.283.5402.689. View

14.

Mita S, Schmidt B, Schon E, DiMauro S, Bonilla E . Detection of "deleted" mitochondrial genomes in cytochrome-c oxidase-deficient muscle fibers of a patient with Kearns-Sayre syndrome. Proc Natl Acad Sci U S A. 1989; 86(23):9509-13. PMC: 298526. DOI: 10.1073/pnas.86.23.9509. View

15.

Moraes C, Ricci E, Petruzzella V, Shanske S, DiMauro S, Schon E . Molecular analysis of the muscle pathology associated with mitochondrial DNA deletions. Nat Genet. 1992; 1(5):359-67. DOI: 10.1038/ng0892-359. View

16.

Schagger H, von Jagow G . Tricine-sodium dodecyl sulfate-polyacrylamide gel electrophoresis for the separation of proteins in the range from 1 to 100 kDa. Anal Biochem. 1987; 166(2):368-79. DOI: 10.1016/0003-2697(87)90587-2. View

17.

Bogenhagen D, Clayton D . Thymidylate nucleotide supply for mitochondrial DNA synthesis in mouse L-cells. Effect of 5-fluorodeoxyuridine and methotrexate in thymidine kinase plus and thymidine kinase minus cells. J Biol Chem. 1976; 251(10):2938-44. View

18.

King M, Attardi G . Post-transcriptional regulation of the steady-state levels of mitochondrial tRNAs in HeLa cells. J Biol Chem. 1993; 268(14):10228-37. View

19.

Bogenhagen D, Lowell C, Clayton D . Mechanism of mitochondrial DNA replication in mouse L-cells. Replication of unicircular dimer molecules. J Mol Biol. 1981; 148(1):77-93. DOI: 10.1016/0022-2836(81)90236-9. View

20.

Tengan C, Moraes C . Duplication and triplication with staggered breakpoints in human mitochondrial DNA. Biochim Biophys Acta. 1998; 1406(1):73-80. DOI: 10.1016/s0925-4439(97)00087-2. View