Mitochondrial DNA alterations and genetic diseases: a review

Lestienne, Patrick; Bataillé, Nelly

doi:10.1016/0753-3322(94)90134-1

Cited by 41 publications

(17 citation statements)

References 92 publications

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“…Human mtDNA lacks the protection of histones and other DNA-binding proteins, and is replicated without an efficient proof-reading and DNA repair system (70)(71)(72)(73). Since the concurrent discovery in 1988 of the first disease-associated large-scale deletions (77) and point mutation (78) of mtDNA, more than 50 pathogenic mtDNA mutations have been found in each type of the genes in mtDNA that are associated with or responsible for specific human diseases (76,(79)(80)(81). The random hit of the naked mtDNA by ROS or free radicals will inevitably cause oxidative damage or mutation with serious consequences (12,16,52).…”

Section: Mitochondria1 Geneticsmentioning

confidence: 99%

Oxidative Stress and Mitochondrial DNA Mutations in Human Aging

Wei¹

1998

Experimental Biology and Medicine

331

197

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The mitochondrial respiratory system is the major intracellular source of the reactive oxygen species (ROS) and free radicals, which are generated as byproducts during the transfer of electrons from NADH or FADH2 to molecular oxygen under normal physiological conditions. An age-dependent increase in the fraction of these toxic byproducts that may escape the defense mechanism of human and animal cells can induce a broad spectrum of oxidative damage to the biomolecules in the mitochondria and the cell as a whole. Abundant evidence has been gathered to suggest that an elevation of oxidative stress and associated oxidative damages gradually occur in the mitochondria of tissue cells during aging. The mitochondrial DNA (mtDNA), while not protected by histones or DNA-binding proteins, is continually exposed to a high steady-state level of ROS and free radicals in the matrix of the mitochondria. Thus, oxidative modification and mutation of mtDNA occur with great ease, and the extent of such alterations of mtDNA increases exponentially with age. The concurrent enhancement of lipid peroxidation and oxidative modification of proteins in mitochondria elicited by the ever-increasing amount of the ROS further aggravate the mutation and oxidative damage to mtDNA in the aging process. The respiratory enzymes containing the defective mtDNA-encoded protein subunits exhibit impaired electron transport function and thereby increase the electron leak and ROS production, which in turn elevate the oxidative stress and oxidative damage to mitochondria. This vicious cycle operates in various tissue cells at different rate and leads to differential accumulation of oxidatively modified and mutant mtDNAs. This may explain the difference in functional decline and structural deterioration of different organs and tissues in human aging. The central role that alterations of the mitochondria and mtDNA may play in aging and age-related degenerative diseases is discussed in relation to the "Mitochondrial theory of aging."

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Section: Mitochondria1 Geneticsmentioning

confidence: 99%

Oxidative Stress and Mitochondrial DNA Mutations in Human Aging

Wei¹

1998

Experimental Biology and Medicine

331

197

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“…Two of these diseases, MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) and MERRF (myoclonic epilepsy and ragged-red fibers) syndromes, are caused mostly by point mutations in the tRNA genes of mtDNA. The patients with MELAS syndrome have an A?G transition at the nucleotide position 3243 in the tRNA Leu (UUR) gene [5,6] and the MERRF patients harbor an A?G mutation at nucleotide position 8344 in the tRNA Lys gene [7,8].…”

Section: Introductionmentioning

confidence: 99%

Detection of DNA mutations associated with mitochondrial diseases by Agilent 2100 bioanalyzer

Lu¹,

Tso²,

Yang³

et al. 2002

Clinica Chimica Acta

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Background: Molecular analysis of mitochondrial DNA (mtDNA) has provided a final diagnosis for many of the mitochondrial diseases. We evaluated the Agilent 2100 bioanalyzer (Agilent Technologies, Palo Alto, CA) to determine whether the system could replace the conventional restriction fragment length polymorphism (RFLP) analysis by the agarose gel electrophoresis for the detection of the mtDNA mutation. Methods: Three members of a family with MELAS syndrome and four members of a family with MERRF syndrome were recruited for this study. After PCR and restriction enzyme digestion, DNA fragments were separated on the Agilent 2100 bioanalyzer in conjunction with the DNA 500 and DNA 1000 Labchip kits and by electrophoresis on precast 3% agarose gels. Results: The data generated by the DNA 500 and DNA 1000 assays using the Agilent 2100 bioanalyzer showed a lower percentage error and a better reproducibility as compared to those obtained by the conventional method. Conclusion: Based on the performance of the bioanalyzer, we suggest that this novel Labchip is adequate to replace the current RFLP analysis by the agarose gel electrophoresis for mtDNA mutation detection. D

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“…Rearrangements causing either addition or deletion of one or more of the sequence repeats can arise. In humans, deletion or duplication between repeated DNA sequences contributes to human genetic disease, both of nuclear genes and in the mitochondrial genome (4,6,7). Several genetically inherited neuromuscular disorders, such as Fragile X, Huntington's disease, and myotonic muscular dystrophy, are associated with expansion of a trinucleotide repeat array (8).…”

mentioning

confidence: 99%

Instability of repetitive DNA sequences: The role of replication in multiple mechanisms

Bzymek

Lovett

2001

Proc. Natl. Acad. Sci. U.S.A.

328

258

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Rearrangements between tandem sequence homologies of various lengths are a major source of genomic change and can be deleterious to the organism. These rearrangements can result in either deletion or duplication of genetic material flanked by direct sequence repeats. Molecular genetic analysis of repetitive sequence instability in Escherichia coli has provided several clues to the underlying mechanisms of these rearrangements. We present evidence for three mechanisms of RecA-independent sequence rearrangements: simple replication slippage, sister-chromosome exchange-associated slippage, and single-strand annealing. We discuss the constraints of these mechanisms and contrast their properties with RecA-dependent homologous recombination. Replication plays a critical role in the two slipped misalignment mechanisms, and difficulties in replication appear to trigger rearrangements via all these mechanisms.

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Mitochondrial DNA alterations and genetic diseases: a review

Cited by 41 publications

References 92 publications

Oxidative Stress and Mitochondrial DNA Mutations in Human Aging

Oxidative Stress and Mitochondrial DNA Mutations in Human Aging

Detection of DNA mutations associated with mitochondrial diseases by Agilent 2100 bioanalyzer

Instability of repetitive DNA sequences: The role of replication in multiple mechanisms

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