The Human Mitochondrial Genome: From Basic Biology to Disease


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The Human Mitochondrial Genome: From Basic Biology to Disease; (PDF) provides a comprehensive; up-to-date examination of human mitochondrial genomics; linking basic research to translational medicine across a range of disease types. Here; international specialists discuss the essential biology of human mitochondrial DNA (mtDNA); including its maintenance; repair; heredity and segregation. Moreover; mtDNA evolution and exploitation; mutations; models and methods for functional studies of mtDNA are dealt with. Disease discussion is supplemented by approaches for treatment strategies; with disease areas discussed including cancer; age-related; mtDNA depletion; neurodegenerative; deletion; and point mutation diseases. Nucleosides supplementation; mitoZNF and mitoTALENs nucleases are among the therapeutic approaches examined in-depth.

With growing funding for mtDNA studies; many clinicians scientists and clinician are turning their attention to mtDNA disease association. This ebook provides the tools and background knowledge required to perform new; impactful research in this stimulating space; from distinguishing a haplogroup-defining variant or disease-related mutation to discovering emerging therapeutic pathways.

  • Outlines and discusses vital research protocols and perspectives for young scientists to pick up
  • Includes an international team of authoritative contributors from basic biologists to clinician-scientists
  • Disease discussion accompanied by diagnostic and therapeutic strategies presently implemented clinically
  • Completely examines recent advances and technological innovations in the field; enabling new mtDNA studies; variant and mutation identification; pathogenic assessment; and therapies

NOTE: The product only includes the ebook; The Human Mitochondrial Genome: From Basic Biology to Disease in PDF. No access codes are included.


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Giuseppe Gasparre, Anna Maria Porcelli


Academic Press




596 pages









Table of contents

Table of contents :
The Human Mitochondrial Genome: From Basic Biology to Disease
Part 1 Biology of human mtDNA1
Part 2 mtDNA evolution and exploitation109
Part 3 mtDNA mutations171
Part 4 mtDNA-determined diseases and therapies351
List of Contributors
Editor’s biographies
Part 1: Biology of human mtDNA
1 mtDNA replication, maintenance, and nucleoid organization
1.1 Human mitochondrial DNA
1.1.1 Characteristics of mitochondrial DNA
1.1.2 Organization of the human mitochondrial genome
1.2 The process of mtDNA replication
1.2.1 Replication mechanisms
1.2.2 Priming
1.2.3 Elongation of mtDNA replication The mitochondrial DNA polymerase POL γ The mitochondrial DNA helicase Twinkle The mitochondrial single-stranded DNA-binding protein The mitochondrial DNA replisome
1.2.4 Termination of mtDNA replication Primer removal Ligation Separation
1.2.5 Other proteins involved in mtDNA replication
1.3 The mitochondrial dNTP supply
1.4 Mitochondrial nucleoids
1.4.1 Nucleoid composition mtDNA Nucleoid-associated proteins
1.4.2 Nucleoid topology
1.4.3 Nucleoid localization
1.4.4 Nucleoid segregation
2 Human mitochondrial transcription and translation
2.1 Introduction
2.2 Coordination of mitochondrial DNA replication and transcription
2.2.1 Overview of mitochondrial DNA replication
2.2.2 The mitochondrial DNA control region The mitochondrial displacement loop The switch between replication and transcription
2.3 Mitochondrial transcription and mitochondrial RNA transactions
2.3.1 Mitochondrial DNA transcription Transcription initiation Transcription elongation Transcription termination
2.3.2 The mitochondrial transcriptome
2.3.3 Mitochondrial RNA-binding proteins and RNA biology Mitochondrial RNA processing Mitochondrial RNA maturation Mitochondrial RNA chaperones and mRNA stability Mitochondrial RNA translation activators
2.4 Mitochondrial translation
2.4.1 The mitochondrial translation machinery Mitoribosome structure Mitoribosome biogenesis
2.4.2 Mitochondrial protein synthesis Mitochondrial translation initiation Mitochondrial translation elongation Mitochondrial translation termination and mitoribosome recycling Cotranslational membrane insertion of newly synthesized polypeptides
2.5 Compartmentalization of gene expression
2.5.1 Mitochondrial DNA nucleoids
2.5.2 Mitochondrial RNA granules
2.5.3 Mitochondrial RNA degradosome
3 Epigenetic features of mitochondrial DNA
3.1 A brief overview of mitochondrial DNA
3.2 Does cytosine methylation occur in mtDNA?
3.3 Bisulfite sequencing analysis of mtDNA
3.4 Estimation of mtDNA methylation with McrBC endonuclease
3.5 Investigation of 5mC in mtDNA by nucleoside liquid chromatography/mass spectrometry
3.6 Epigenetic features of mammalian mtDNA
4 Heredity and segregation of mtDNA
4.1 Introduction
4.2 General principles of mtDNA segregation
4.3 Uniparental maternal inheritance of mitochondrial DNA
4.4 Paternal leakage during mtDNA inheritance
4.5 mtDNA mutations—homoplasmy versus heteroplasmy
4.6 Germline segregation of mtDNA mutations and the genetic bottleneck
4.7 Purifying selection against mtDNA mutations in the germline
4.8 Somatic mtDNA mutations and clonal expansion
4.9 Conclusions
Part 2: mtDNA evolution and exploitation
5 Haplogroups and the history of human evolution through mtDNA
5.1 Early restriction fragment length polymorphism studies
5.2 The advent of polymerase chain reaction in the mtDNA world
5.3 Haplogroup nomenclature of human mtDNA
5.4 The survey of entire mitogenomes
5.5 The “Out of Africa Exit”
5.6 The first peopling of the Americas
5.7 The peopling of an island in the Mediterranean Sea
6 Human nuclear mitochondrial sequences (NumtS)
6.1 NumtS definition and introduction
6.2 NumtS discovery
6.3 NumtS detection
6.3.1 In silico human NumtS detection based on reference genomes
6.3.2 Detection of sample-specific NumtS
6.3.3 In vitro NumtS identification
6.4 Numtogenesis: Mechanisms of NumtS insertion
6.5 NumtS variability and polymorphisms
6.6 The role of NumtS in mtDNA sequencing and disease
6.7 NumtS annotation: Current and future roles of NumtS
7 mtDNA exploitation in forensics
7.1 Introduction
7.2 mtDNA typing in historical forensic identification
7.3 mtDNA sequencing in forensic practice
7.3.1 Extraction
7.3.2 mtDNA quantification by real-time PCR
7.3.3 Targeted region and PCR amplification
7.3.4 mtDNA sequencing
7.3.5 Rapid screening assay for mtDNA type
7.3.6 Massive parallel sequencing of full mitochondrial genome
7.4 Data analysis, alignment, and haplotype notation
7.4.1 Alignment
7.4.2 Notation for forensics purposes
7.4.3 Heteroplasmy
7.5 Interpretation of mtDNA results
7.5.1 Sequence comparison
7.5.2 Statistical evaluation: weight of evidence
7.6 Mitochondrial DNA population databases used in forensics
7.7 Guidelines and recommendations
Part 3: mtDNA mutations
8 Human mitochondrial DNA repair
8.1 Base excision repair
8.2 Repair of bulky lesions
8.3 Double-strand break repair
8.4 Mismatch repair
8.5 Translesion synthesis
8.6 Concluding remarks
9 Mechanisms of onset and accumulation of mtDNA mutations
9.1 Mitochondrial DNA abnormalities
9.1.1 Primary mitochondrial DNA mutants Rearrangements: deletions and duplications Mitochondrial DNA point mutants
9.2 Criteria to designate a primary mtDNA mutation as pathological
9.3 Clinical and biochemical correlates
9.4 Mitochondrial genetic rules
9.5 Selection and counterselection of deleterious mtDNA variants
9.5.1 Phenotypic selection of fully functional mtDNAs
9.5.2 Propagation of dysfunctional mitochondria—misuse of the natural process of coupling mitochondrial mass to energy demand
9.5.3 Selfish mechanisms
9.5.4 Metabolic configuration and nutrient availability
9.6 Genetic drift
9.7 Mitochondrial DNA selection—more or less?
9.8 Stable heteroplasmy—the persistence of a fixed proportion of mutant and wild-type mtDNA
9.9 Mitochondrial DNA maintenance disorders
9.10 Ribonucleotide incorporation—a new mtDNA abnormality and a potential precursor or mitigator of mtDNA deletions and dep…
9.11 Overlaps between nuclear defects in the mtDNA maintenance system and primary mtDNA mutants
9.12 A mitochondrial DNA network and its implications for heteroplasmy
10 Mitochondrial DNA mutations and aging
10.1 Introduction
10.2 Old and new mitochondrial theories of aging—how changes in mtDNA contribute to aging?
10.3 Mitochondrial genetics from the perspective of aging
10.4 mtDNA deletions and aging
10.4.1 The origin of mtDNA deletions
10.4.2 How do mtDNA deletions expand during aging?
10.4.3 Do mtDNA deletions play a role in aging?
10.5 mtDNA point mutations
10.5.1 MtDNA point mutations occur during aging
10.5.2 The origin of somatic mtDNA point mutations during aging: oxidative stress versus replication errors?
10.5.3 Oxidative damage
10.5.4 DNA polymerases
10.5.5 Is mtDNA susceptible to oxidative damage?
10.5.6 Origin of mtDNA mutations—evidence from animal models
10.5.7 When are point mutations generated, and how do they expand?
10.6 How do somatic mtDNA mutations lead to aging?
10.6.1 Tissue-specific consequences of mtDNA mutations during aging
10.7 mtDNA mutations and aging of stem cells
10.8 Conclusions
11 Methods for the identification of mitochondrial DNA variants
11.1 Introduction to human mtDNA variants detection
11.2 Techniques for detecting mitochondrial variants
11.2.1 Polymerase chain reaction–based methods and mtDNA rearrangements detection Polymerase chain reaction restriction fragment length polymorphism Southern blotting and long-range polymerase chain reaction Pyrosequencing Quantitative polymerase chain reaction Single molecule–based detection techniques
11.2.2 Broad-spectrum techniques for detection of variants in whole mtDNA genomes Single-strand conformation polymorphism Denaturing high-performance liquid chromatography Sanger sequencing Microarrays Second-generation sequencing Third-generation sequencing
11.3 Challenges in mitochondrial variant studies
11.3.1 Mitochondrial DNA isolation
11.3.2 NumtS contamination
11.4 Bioinformatics strategies to detect mitochondrial variants and heteroplasmy
11.4.1 Reads mapping and genome assembly
11.4.2 Mitochondrial variant calling
11.4.3 Mitochondrial phylogenetic analysis
12 Bioinformatics resources, databases, and tools for human mtDNA
12.1 Introduction to human mtDNA variability (Wallace DC and Attimonelli M)
12.2 Human mtDNA genomes and variants
12.2.1 Primary databases: GenBank/ENA/DDBJ (Attimonelli M)
12.2.2 MITOMAP (Lott MT, Procaccio V, and Zhang S) Variant status in MITOMAP Haplogroup assignment in MITOMAP Allele search function in MITOMAP Analyzing mtDNA variability using MITOMASTER MitoTIP
12.3 The Human MitoCompendium: HmtDB, HmtVar, and HmtPhenome (Attimonelli M, Preste R, and Vitale O)
12.3.1 HmtDB HmtDB API
12.3.2 HmtVar (Preste R, Vitale O, and Attimonelli M) HmtVar variants pathogenicity assessment (Attimonelli M and Vitale O)
12.3.3 HmtPhenome (Preste R and Attimonelli M)
12.4 MSeqDR—Mitochondrial Disease Sequence Data Resource (MSeqDR) Consortium (Lott M)
12.4.1 MvTool
12.5 Other specialized human mitochondrial databases (Attimonelli M and Preste R)
12.6 Tools for variant annotations (Attimonelli M and Preste R)
12.6.1 HmtNote
12.6.2 HaploGrep
12.6.3 MitImpact3D
12.6.4 PON-mt-tRNA [87]
12.7 Nuclear encoded mitochondrial genes databases (Vitale O and Attimonelli M)
Further reading
13 Methods and models for functional studies on mtDNA mutations
13.1 Introduction
13.2 Models for the study of mtDNA mutations: in vitro models
13.2.1 Human primary cell lines
13.2.2 Cybrids
13.2.3 Patient-specific induced pluripotent stem cells
13.2.4 Yeast
13.3 Animal models
13.3.1 Caenorhabditis elegans
13.3.2 Drosophila melanogaster ATP6 mutant CoI mutants ND2 mutants CoII mutant
13.3.3 Mice mtDNA deletions mt-Co1 mt-Nd6 mt-tK (tRNALys) mt-tA (tRNAAla) PolgA Twnk Mgme1
13.4 Methods for assessment of functional defects induced by mtDNA alterations
13.4.1 OXPHOS complexes activity Spectrophotometric methods Sample preparation NADH:ubiquinone oxidoreductase activity (CI activity) Succinate:ubiquinone oxidoreductase activity (CII activity) Ubiquinol:cytochrome c oxidoreductase activity (CIII activity) Cytochrome c oxidoreductase activity (CIV activity) NADH:cytochrome c oxidoreductase (CI+III activity) Succinate:cytochrome c oxidoreductase (CII+III activity) Hydrolytic activity of ATP synthase (CV activity) Citrate synthase activity Immunocapture-based assays
13.4.2 Oxygen consumption Classic Clark-type electrode methods High-resolution respirometry Microrespirometry on multiwell plate
13.4.3 Determination of mitochondrial membrane potential
13.4.4 ATP production
13.4.5 Reactive oxygen species measurement
13.4.6 Blue Native Polyacrylamide Gel Electrophoresis
Part 4: mtDNA-determined diseases and therapies
14 Mitochondrial DNA-related diseases associated with single large-scale deletions and point mutations
14.1 Clinical syndromes of mitochondrial DNA-related diseases associated with single large-scale deletions and point mutations
14.1.1 Exercise intolerance
14.1.2 Kearns-Sayre syndrome
14.1.3 Leber-dystonia
14.1.4 Leber hereditary optic neuropathy
14.1.5 Maternally inherited diabetes and deafness
14.1.6 Maternally inherited Leigh syndrome
14.1.7 Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes
14.1.8 Mitochondrial myopathy and cardiomyopathy
14.1.9 Myoclonic epilepsy with ragged red fibers
14.1.10 Neurogenic muscle weakness, ataxia, retinitis pigmentosa
14.1.11 Nonsyndromic sensorineural hearing loss
14.1.12 Pearson marrow pancreas syndrome
14.1.13 Progressive external ophthalmoplegia/progressive external ophthalmoplegia plus
14.1.14 Reversible infantile mitochondrial myopathy
14.2 Molecular genetics of mitochondrial DNA single large-scale deletions and point mutations
14.3 Diagnostic approach to mitochondrial DNA-related diseases associated with single large-scale deletions and point mutations
14.3.1 Laboratory tests
14.3.2 Neuroimaging
14.3.3 Skeletal muscle histochemistry, electron microscopy, and respiratory chain biochemistry
14.3.4 Genetic testing
14.4 Management of mitochondrial DNA-related diseases associated with single large-scale deletions and point mutations
14.4.1 Supportive therapies
14.4.2 Vitamins and cofactors
14.4.3 Emerging therapies
14.4.4 Reproductive options
15 Nuclear genetic disorders of mitochondrial DNA gene expression
15.1 Introduction
15.2 Mechanisms of mtDNA replication
15.3 Defects of mtDNA replication
15.3.1 Mutations in POLG
15.3.2 Mutations in TWNK
15.3.3 Mutations in DNA2
15.3.4 Mutations in MGME1
15.4 Maintenance of dNTP pool
15.5 Defects of the dNTP salvage pathway and nucleotide metabolism
15.5.1 Mutations in TK2
15.5.2 Mutations in RRM2B
15.5.3 Mutations in MPV17
15.6 Mechanism of mitochondrial transcription
15.7 Defects of mitochondrial transcription
15.7.1 Mutations in TFAM
15.7.2 Mutations in TFB2M
15.8 Transcript processing
15.9 Defects of maturation of pre mt-RNA
15.9.1 Mutations in RNase P complex (MRPP1, 2, 3)
15.9.2 Mutations in RNase Z (ELAC2)
15.10 mt-mRNA maturation and turnover
15.11 Defects of mt-mRNA maturation and turnover
15.11.1 Mutations in MTPAP
15.11.2 Mutations in LRPPRC
15.12 mt-tRNA maturation
15.13 Defects of mt-tRNA maturation and modification
15.13.1 Mutations in TRNT1
15.13.2 Mutations in PUS1
15.13.3 Mutations in MTO1 and GTPBP3
15.13.4 Mutations in TRMU
15.13.5 Mutations in TRIT1
15.13.6 Mutations in mitochondrial aminoacyl-tRNA synthetases
15.14 mt-rRNA maturation
15.15 Defects of mt-rRNA maturation, modification, and stability
15.15.1 Mutations in MRM2
15.15.2 Mutations in FASTKD2
15.16 Mechanism of mitochondrial translation
15.17 Mutations in mitoribosomal proteins
15.18 Defects of translation initiation
15.18.1 Mutations in MTFMT
15.18.2 Mutations in RMND1
15.19 Defects of translation elongation
15.19.1 Mutations in GFM1
15.19.2 Mutations in TSFM
15.20 Defects of translation termination and mitoribosome recycling
15.20.1 Mutations in C12orf65
15.20.2 Mutations in GFM2
15.21 Defects of translational activation and coupling
15.21.1 Mutations in TACO1
15.21.2 Mutations in COA3 and C12orf62
15.22 IMM insertion of mtDNA-encoded OXPHOS proteins
15.22.1 Mutations in OXA1L
16 mtDNA maintenance: disease and therapy
16.1 Introduction
16.2 Defects in mtDNA replisome
16.3 Defects in mitochondrial nucleotides pool balance
16.4 Defects in mitochondrial dynamics
16.5 Defect in nucleoid proteins
16.6 Experimental therapies
16.7 General pharmacological approaches
16.7.1 Targeting mitochondrial biogenesis
16.7.2 Targeting mTOR pathway
16.8 Disease-tailored therapies
16.8.1 Nucleos(t)ide supplementation therapies
16.8.2 Clearance of toxic metabolites
16.8.3 Enzyme replacement
16.8.4 Platelet infusion
16.8.5 Hematopoietic stem cell transplantation
16.8.6 Erythrocytes encapsulated thymidine phosphorylase
16.8.7 Liver transplant: tissue-specific disorder and source of enzyme replacement
16.8.8 Gene therapy
17 mtDNA mutations in cancer
17.1 The landscape of mtDNA mutations in cancer
17.2 Functional effects of mtDNA mutations in solid cancers
17.2.1 mtDNA mutations and metabolic adaptation
17.2.2 MtDNA mutations and hypoxic stress
17.2.3 mtDNA mutations and metastatic progression
17.3 The fate of severely pathogenic mtDNA mutations in progressing solid tumors
17.3.1 Molecular mechanisms behind selection and purification of mtDNA mutations in cancer
17.3.2 Compensatory mechanisms to overcome mitochondrial dysfunction
17.3.3 MtDNA mutations in oncocytomas: an exception from the rule
17.4 Clinical potential of cancer-associated mtDNA mutations
17.4.1 MtDNA mutations and cancer treatment Chemotherapy Radiotherapy Interventions in cancer therapy based on mitochondrial functional status
17.4.2 Cancer-specific mtDNA mutations as markers of tumor progression
17.5 Insights from next generation sequencing and bioinformatics approaches
17.5.1 Technical pitfalls and false discoveries of the past
17.5.2 Methodological recommendations for mtDNA mutation analysis in the advent of next generation sequencing in oncology
17.5.3 The influence of big data on what we know on mtDNA mutations in cancer
18 MitoTALENs for mtDNA editing
18.1 Introduction
18.2 The use of specific endonucleases to target mtDNA
18.3 The use of mitoTALENs to target mtDNA
18.4 Structure of mitoTALENs
18.5 MitoTALENs targeting mutations in cybrids
18.6 MitoTALENs in a heteroplasmic mouse model carrying a tRNAAla mutation
18.7 MitoTALENs and induced pluripotent stem cells
18.8 Other uses of mitoTALENs
18.8.1 MitoTALENs in germline transmission MitoTALENs to study mtDNA replication
18.8.2 MitoTevTAL nuclease
18.9 Pros and cons of using mitoTALENs for gene therapy
18.9.1 Specificity and mtDNA depletion
18.9.2 Off-target sequences in the nucleus
18.9.3 Easy design of new recognition sites
18.9.4 MitoTALEN gene size
18.9.5 The future of mitoTALENs as therapy
19 Mitochondrially targeted zinc finger nucleases
19.1 Introduction
19.2 Zinc finger domain—structure and interaction with DNA
19.3 Designer zinc fingers
19.4 Chimeric zinc finger proteins—birth of zinc finger nuclease
19.5 Manipulation of the mammalian mitochondrial genome with mtZFNs
19.5.1 The first step
19.5.2 In vivo use of mtZFNs
19.6 Concluding remarks
20 Mitochondrial movement between mammalian cells: an emerging physiological phenomenon
20.1 Introduction
20.2 Cell-to-cell transfer of mitochondria with mtDNA: a brief overview
20.3 Translational benefits of mitochondrial transfer
20.3.1 Mitochondrial transfer between cells Mitochondrial transfer into tumor cells Mitochondrial transfer into normal cells Mitochondrial donation therapy to prevent mitochondrial diseases in offspring
20.3.2 Transfer of isolated mitochondria Ischemic heart disease Neurodegenerative disorders and ischemic stroke Behavioral disorders Cancer sensitization to treatment
20.4 Mechanisms of mitochondrial transfer
20.5 Mito-nuclear crosstalk: potential consequences of mitochondrial transfer/transplantation
20.6 Concluding statement
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