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      Mitochondrial DNA replication in mammalian cells: overview of the pathway

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      Publication date (Electronic):
      Journal: Essays in Biochemistry
      Publisher: Portland Press Ltd.
      Keywords: DNA replication, DNA polymerase, DNA helicase, mitochondrion

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          Abstract

          Mammalian mitochondria contain multiple copies of a circular, double-stranded DNA genome and a dedicated DNA replication machinery is required for its maintenance. Many disease-causing mutations affect mitochondrial replication factors and a detailed understanding of the replication process may help to explain the pathogenic mechanisms underlying a number of mitochondrial diseases. We here give a brief overview of DNA replication in mammalian mitochondria, describing our current understanding of this process and some unanswered questions remaining.

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          Maintenance and Expression of Mammalian Mitochondrial DNA.

          Claes M. Gustafsson, Maria Falkenberg, Nils-Göran Larsson (2016)
          Mammalian mitochondrial DNA (mtDNA) encodes 13 proteins that are essential for the function of the oxidative phosphorylation system, which is composed of four respiratory-chain complexes and adenosine triphosphate (ATP) synthase. Remarkably, the maintenance and expression of mtDNA depend on the mitochondrial import of hundreds of nuclear-encoded proteins that control genome maintenance, replication, transcription, RNA maturation, and mitochondrial translation. The importance of this complex regulatory system is underscored by the identification of numerous mutations of nuclear genes that impair mtDNA maintenance and expression at different levels, causing human mitochondrial diseases with pleiotropic clinical manifestations. The basic scientific understanding of the mechanisms controlling mtDNA function has progressed considerably during the past few years, thanks to advances in biochemistry, genetics, and structural biology. The challenges for the future will be to understand how mtDNA maintenance and expression are regulated and to what extent direct intramitochondrial cross talk between different processes, such as transcription and translation, is important.
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            Human mitochondrial DNA deletions associated with mutations in the gene encoding Twinkle, a phage T7 gene 4-like protein localized in mitochondria.

            G Comi, R. L. Croxen, M. Tariq … (2001)
            The gene products involved in mammalian mitochondrial DNA (mtDNA) maintenance and organization remain largely unknown. We report here a novel mitochondrial protein, Twinkle, with structural similarity to phage T7 gene 4 primase/helicase and other hexameric ring helicases. Twinkle colocalizes with mtDNA in mitochondrial nucleoids. Screening of the gene encoding Twinkle in individuals with autosomal dominant progressive external ophthalmoplegia (adPEO), associated with multiple mtDNA deletions, identified 11 different coding-region mutations co-segregating with the disorder in 12 adPEO pedigrees of various ethnic origins. The mutations cluster in a region of the protein proposed to be involved in subunit interactions. The function of Twinkle is inferred to be critical for lifetime maintenance of human mtDNA integrity.
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              Cross-strand binding of TFAM to a single mtDNA molecule forms the mitochondrial nucleoid.

              Christian Kukat, Karen M Davies, Christian A. Wurm … (2015)
              Mammalian mitochondrial DNA (mtDNA) is packaged by mitochondrial transcription factor A (TFAM) into mitochondrial nucleoids that are of key importance in controlling the transmission and expression of mtDNA. Nucleoid ultrastructure is poorly defined, and therefore we used a combination of biochemistry, superresolution microscopy, and electron microscopy to show that mitochondrial nucleoids have an irregular ellipsoidal shape and typically contain a single copy of mtDNA. Rotary shadowing electron microscopy revealed that nucleoid formation in vitro is a multistep process initiated by TFAM aggregation and cross-strand binding. Superresolution microscopy of cultivated cells showed that increased mtDNA copy number increases nucleoid numbers without altering their sizes. Electron cryo-tomography visualized nucleoids at high resolution in isolated mammalian mitochondria and confirmed the sizes observed by superresolution microscopy of cell lines. We conclude that the fundamental organizational unit of the mitochondrial nucleoid is a single copy of mtDNA compacted by TFAM, and we suggest a packaging mechanism.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Essays Biochem
                Journal ID (iso-abbrev): Essays Biochem
                Journal ID (hwp): ppebio
                Journal ID (publisher-id): BSE
                Title: Essays in Biochemistry
                Publisher: Portland Press Ltd.
                ISSN (Print): 0071-1365
                ISSN (Electronic): 1744-1358
                Publication date (Electronic): 07 June 2018
                Publication date Collection: 20 July 2018
                Volume: 62
                Issue: 3 , Mitochondrial Diseases
                Pages: 287-296
                Affiliations
                Department of Medical Biochemistry and Cell Biology, University of Gothenburg, P.O. Box 440, 405 30 Gothenburg, Sweden
                Author notes
                Correspondence: Maria Falkenberg ( maria.falkenberg@ 123456medkem.gu.se )
                Article
                DOI: 10.1042/EBC20170100
                PMC ID: 6056714
                PubMed ID: 29880722
                SO-VID: 60b8dfb0-ec98-4ec0-8161-fe18c8972661
                Copyright © © 2018 The Author(s).
                License:

                This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY-NC-ND).

                History
                Date received : 06 April 2018
                Date revision received : 18 May 2018
                Date accepted : 21 May 2018
                Page count
                Pages: 10
                Categories
                Subject: Review Articles
                Subject: Review Article
                Subject: 11

                Keywords: dna replication,dna polymerase,dna helicase,mitochondrion
                Data availability:
                Keywords: dna replication, dna polymerase, dna helicase, mitochondrion

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