Inherited Mitochondrial Genomic Instability and Chemical Exposures

Overview

Journal Toxicology

Publisher Elsevier

Specialty Toxicology

Date 2017 Jul 31

PMID 28756246

Citations 9

Authors

Sherine S L Chan

Affiliations

Soon will be listed here.

Abstract

There are approximately 1500 proteins that are needed for mitochondrial structure and function, most of which are encoded in the nuclear genome (Calvo et al., 2006). Each mitochondrion has its own genome (mtDNA), which in humans encodes 13 polypeptides, 22 tRNAs and 2 rRNAs required for oxidative phosphorylation. The mitochondrial genome of humans and most vertebrates is approximately 16.5kbp, double-stranded, circular, with few non-coding bases. Thus, maintaining mtDNA stability, that is, the ability of the cell to maintain adequate levels of mtDNA template for oxidative phosphorylation is essential and can be impacted by the level of mtDNA mutation currently within the cell or mitochondrion, but also from errors made during normal mtDNA replication, defects in mitochondrial quality control mechanisms, and exacerbated by exposures to exogenous and/or endogenous genotoxic agents. In this review, we expand on the origins and consequences of mtDNA instability, the current state of research regarding the mechanisms by which mtDNA instability can be overcome by cellular and chemical interventions, and the future of research and treatments for mtDNA instability.

Citing Articles

Combined Effects of Fluoride and Arsenic on Mitochondrial Function in the Liver of Rat.

Khan H, Verma Y, Rana S Appl Biochem Biotechnol. 2023; 195(11):6856-6866.

PMID: 36947368 DOI: 10.1007/s12010-023-04401-4.

Mitochondrial toxicity evaluation of traditional Chinese medicine injections with a dual approach.

Shen Y, Guo K, Ma A, Huang Z, Du J, Chen J Front Pharmacol. 2022; 13:1039235.

PMID: 36408232 PMC: 9667049. DOI: 10.3389/fphar.2022.1039235.

Case Report: Evidences of myasthenia and cerebellar atrophy in a chinese patient with novel compound heterozygous variants.

Liu L, Su R, Huang P, Li X, Xiong J, Xiao Y Front Genet. 2022; 13:947886.

PMID: 36035138 PMC: 9402982. DOI: 10.3389/fgene.2022.947886.

Identification of a Somatic Mutation-Derived Long Non-Coding RNA Signatures of Genomic Instability in Renal Cell Carcinoma.

Fang X, Liu X, Lu L, Liu G Front Oncol. 2021; 11:728181.

PMID: 34676164 PMC: 8523920. DOI: 10.3389/fonc.2021.728181.

PCR-Based Determination of Mitochondrial DNA Copy Number in Multiple Species.

Leuthner T, Hartman J, Ryde I, Meyer J Methods Mol Biol. 2021; 2310:91-111.

PMID: 34096001 DOI: 10.1007/978-1-0716-1433-4_8.

References

Matsushima Y, Farr C, Fan L, Kaguni L . Physiological and biochemical defects in carboxyl-terminal mutants of mitochondrial DNA helicase. J Biol Chem. 2008; 283(35):23964-71. PMC: 2527111. DOI: 10.1074/jbc.M803674200. View

Stewart J, Chinnery P . The dynamics of mitochondrial DNA heteroplasmy: implications for human health and disease. Nat Rev Genet. 2015; 16(9):530-42. DOI: 10.1038/nrg3966. View

Gonzalez-Vioque E, Blazquez A, Fernandez-Moreira D, Bornstein B, Bautista J, Arpa J . Association of novel POLG mutations and multiple mitochondrial DNA deletions with variable clinical phenotypes in a Spanish population. Arch Neurol. 2006; 63(1):107-11. DOI: 10.1001/archneur.63.1.107. View

Korhonen J, Pande V, Holmlund T, Farge G, Pham X, Nilsson L . Structure-function defects of the TWINKLE linker region in progressive external ophthalmoplegia. J Mol Biol. 2008; 377(3):691-705. DOI: 10.1016/j.jmb.2008.01.035. View

Koczor C, Torres R, Fields E, Qin Q, Park J, Ludaway T . Transgenic mouse model with deficient mitochondrial polymerase exhibits reduced state IV respiration and enhanced cardiac fibrosis. Lab Invest. 2012; 93(2):151-8. PMC: 3556371. DOI: 10.1038/labinvest.2012.146. View

Zapico S, Ubelaker D . mtDNA Mutations and Their Role in Aging, Diseases and Forensic Sciences. Aging Dis. 2013; 4(6):364-80. PMC: 3843653. DOI: 10.14336/AD.2013.0400364. View

Amato P, Tachibana M, Sparman M, Mitalipov S . Three-parent in vitro fertilization: gene replacement for the prevention of inherited mitochondrial diseases. Fertil Steril. 2014; 101(1):31-5. PMC: 4005382. DOI: 10.1016/j.fertnstert.2013.11.030. View

Valente W, Ericson N, Long A, White P, Marchetti F, Bielas J . Mitochondrial DNA exhibits resistance to induced point and deletion mutations. Nucleic Acids Res. 2016; 44(18):8513-8524. PMC: 5062989. DOI: 10.1093/nar/gkw716. View

Facucho-Oliveira J, Alderson J, Spikings E, Egginton S, St John J . Mitochondrial DNA replication during differentiation of murine embryonic stem cells. J Cell Sci. 2007; 120(Pt 22):4025-34. DOI: 10.1242/jcs.016972. View

10.

Kasiviswanathan R, Longley M, Chan S, Copeland W . Disease mutations in the human mitochondrial DNA polymerase thumb subdomain impart severe defects in mitochondrial DNA replication. J Biol Chem. 2009; 284(29):19501-10. PMC: 2740576. DOI: 10.1074/jbc.M109.011940. View

11.

Wallace D . Mitochondrial diseases in man and mouse. Science. 1999; 283(5407):1482-8. DOI: 10.1126/science.283.5407.1482. View

12.

Dillon L, Hida A, Garcia S, Prolla T, Moraes C . Long-term bezafibrate treatment improves skin and spleen phenotypes of the mtDNA mutator mouse. PLoS One. 2012; 7(9):e44335. PMC: 3433471. DOI: 10.1371/journal.pone.0044335. View

13.

Goffart S, Cooper H, Tyynismaa H, Wanrooij S, Suomalainen A, Spelbrink J . Twinkle mutations associated with autosomal dominant progressive external ophthalmoplegia lead to impaired helicase function and in vivo mtDNA replication stalling. Hum Mol Genet. 2008; 18(2):328-40. PMC: 2638771. DOI: 10.1093/hmg/ddn359. View

14.

Calvo S, Jain M, Xie X, Sheth S, Chang B, Goldberger O . Systematic identification of human mitochondrial disease genes through integrative genomics. Nat Genet. 2006; 38(5):576-82. DOI: 10.1038/ng1776. View

15.

Tachibana M, Amato P, Sparman M, Woodward J, Melguizo Sanchis D, Ma H . Towards germline gene therapy of inherited mitochondrial diseases. Nature. 2012; 493(7434):627-31. PMC: 3561483. DOI: 10.1038/nature11647. View

16.

Jo A, Ham S, Lee G, Lee Y, Kim S, Lee Y . Efficient Mitochondrial Genome Editing by CRISPR/Cas9. Biomed Res Int. 2015; 2015:305716. PMC: 4581504. DOI: 10.1155/2015/305716. View

17.

McHugh J, Lonergan R, Howley R, ORourke K, Taylor R, Farrell M . Sensory ataxic neuropathy dysarthria and ophthalmoparesis (SANDO) in a sibling pair with a homozygous p.A467T POLG mutation. Muscle Nerve. 2009; 41(2):265-9. DOI: 10.1002/mus.21494. View

18.

Alsdorf R, Wyszynski D . Teratogenicity of sodium valproate. Expert Opin Drug Saf. 2005; 4(2):345-53. DOI: 10.1517/14740338.4.2.345. View

19.

Saneto R, Cohen B, Copeland W, Naviaux R . Alpers-Huttenlocher syndrome. Pediatr Neurol. 2013; 48(3):167-78. PMC: 3578656. DOI: 10.1016/j.pediatrneurol.2012.09.014. View

20.

Chan S, Longley M, Copeland W . The common A467T mutation in the human mitochondrial DNA polymerase (POLG) compromises catalytic efficiency and interaction with the accessory subunit. J Biol Chem. 2005; 280(36):31341-6. DOI: 10.1074/jbc.M506762200. View