Inherited Mitochondrial Diseases of DNA Replication*

Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Annual Review of Medicine (Impact Factor: 12.93). 02/2008; 59(1):131-46. DOI: 10.1146/
Source: PubMed


Mitochondrial genetic diseases can result from defects in mitochondrial DNA (mtDNA) in the form of deletions, point mutations, or depletion, which ultimately cause loss of oxidative phosphorylation. These mutations may be spontaneous, maternally inherited, or a result of inherited nuclear defects in genes that maintain mtDNA. This review focuses on our current understanding of nuclear gene mutations that produce mtDNA alterations and cause mitochondrial depletion syndrome (MDS), progressive external ophthalmoplegia (PEO), ataxia-neuropathy, or mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). To date, all of these etiologic nuclear genes fall into one of two categories: genes whose products function directly at the mtDNA replication fork, such as POLG, POLG2, and TWINKLE, or genes whose products supply the mitochondria with deoxynucleotide triphosphate pools needed for DNA replication, such as TK2, DGUOK, TP, SUCLA2, ANT1, and possibly the newly identified MPV17.

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Available from: William C Copeland, Dec 20, 2013
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    • "Furthermore, unlike PolG- END, mitochondrial extracts from PolG-p53 MKO failed to repair mutations in vitro in the primer extensionmutation repair assay (Additional file 1: Figure S6F). Thus, exercise-induced maintenance of mtDNA stability is contingent on mitochondrially localized p53 and represents a viable therapy for pre-symptomatic patients carrying POLG1 exonuclease domain mutations known to cause pathology[35]. "
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    ABSTRACT: Background: Human genetic disorders and transgenic mouse models have shown that mitochondrial DNA (mtDNA) mutations and telomere dysfunction instigate the aging process. Epidemiologically, exercise is associated with greater life expectancy and reduced risk of chronic diseases. While the beneficial effects of exercise are well established, the molecular mechanisms instigating these observations remain unclear. Results: Endurance exercise reduces mtDNA mutation burden, alleviates multisystem pathology, and increases lifespan of the mutator mice, with proofreading deficient mitochondrial polymerase gamma (POLG1). We report evidence for a POLG1-independent mtDNA repair pathway mediated by exercise, a surprising notion as POLG1 is canonically considered to be the sole mtDNA repair enzyme. Here, we show that the tumor suppressor protein p53 translocates to mitochondria and facilitates mtDNA mutation repair and mitochondrial biogenesis in response to endurance exercise. Indeed, in mutator mice with muscle-specific deletion of p53, exercise failed to prevent mtDNA mutations, induce mitochondrial biogenesis, preserve mitochondrial morphology, reverse sarcopenia, or mitigate premature mortality. Conclusions: Our data establish a new role for p53 in exercise-mediated maintenance of the mtDNA genome and present mitochondrially targeted p53 as a novel therapeutic modality for diseases of mitochondrial etiology.
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    • "In addition to direct mutations in mtDNA, mtDNA dysfunction can also be caused by mutations in nDNA (Figure 1). MtDNA-related nuclear genes that cause disease mainly affect mtDNA replication and copy number maintenance, and they fall into two categories: those that directly affect the mtDNA replication fork and mutations in genes that are involved in the supply of nucleotides for mtDNA replication (such as mitochondrial thymidine kinase TK2, the deoxyguanosine kinase dGK, and adenine nucleotide transporter ANT1) (Copeland, 2008). The effects of these mutations are sometimes called secondary mtDNA defects. "
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    ABSTRACT: Mitochondrial diseases are a heterogeneous group of disorders that are currently the focus of intense research. The many cell functions performed by mitochondria include ATP production, calcium homeostasis, and apoptosis. One of the unique properties of mitochondria is the existence of a separate mitochondrial genome (mitochondrial DNA, mtDNA) found in varying copy numbers and containing 37 genes, 13 of them encoding proteins. All 13 mitochondrially encoded proteins form part of oxidative phosphorylation complexes through combination with approximately 100 nuclear DNA-encoded proteins. Coregulation of nDNA and mtDNA is therefore essential for mitochondrial function, and this coregulation contributes to the heterogeneity and complexity observed in mitochondrial disorders. In recent times, significant advances have been made in our understanding of mtDNA-related disorders. A comprehensive review of these studies will benefit both current and new researchers and clinicians involved in the field. This review examines the major types of mtDNA-related defects and their pathogenic mechanisms, with a special emphasis on the heterogeneity of mitochondrial disorders. Potential treatment strategies specialized for each of the disorders, including the hormone melatonin and the recent advances in gene therapy, related to their potential applications for the management of the primary mtDNA disorders are also discussed.
    Full-text · Article · Aug 2015 · Turkish Journal of Biology
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    • "While individual deletions have little effect on mtDNA stability, loss of both genes leads to frequent and rapid mtDNA depletion [53]. In humans, mitochondrial genetic diseases linked with nuclear genes affect replication of mtDNA either directly at the replication fork or by nucleotide supply [54]. In view of RECQ4's possible role during replication, it is not surprising that symptoms associated with deficiency in some of these genes (POLG, TWINKLE) show similarity to those of subsets of RTS patients, including mental retardation associated with atrophy of the brain [55] [56] [57]. "
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    ABSTRACT: The RECQ4 protein belongs to the RecQ helicase family, which plays crucial roles in genome maintenance. Mutations in the RECQ4 gene are associated with three insidious hereditary disorders: Rothmund-Thomson, Baller-Gerold, and RAPADILINO syndromes. These syndromes are characterized by growth deficiency, radial ray defects, red rashes, and higher predisposition to malignancy, especially osteosarcomas. Within the RecQ family, RECQ4 is the least characterized, and its role in DNA replication and repair remains unknown. We have identified several DNA binding sites within RECQ4. Two are located at the N-terminus and one is located within the conserved helicase domain. N-terminal domains probably cooperate with one another and promote the strong annealing activity of RECQ4. Surprisingly, the region spanning 322-400aa shows a very high affinity for branched DNA substrates, especially Holliday junctions. This study demonstrates biochemical activities of RECQ4 that could be involved in genome maintenance and suggest its possible role in processing replication and recombination intermediates. Copyright © 2015 Elsevier B.V. All rights reserved.
    Full-text · Article · Feb 2015 · DNA Repair
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