Mitochondrial Diseases E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Serie: Life Science Research Fundamentals
• Sprache: Englisch

Seitenzahl: 269

Veröffentlichungsjahr: 2013

Beschreibung

This collection of reviews and protocols provides the reader with an introduction to the current state of knowledge on how various diseases are related to mitochondrial dysfunction. Mitochondria contain their own genome, a small, circular double-stranded DNA (mtDNA), and alterations in mtDNA may play an important role in the multistep carcinogenesis of at least some types of human cancer. In addition to mutations of mtDNA, many mitochondrial syndromes are due to abnormalities in nuclear genes related to oxidative phosphorylation (OXPHOS). Mitochondrial tRNA (MTT) gene mutations are an important cause of human morbidity and are associated with a wide range of pathology, from isolated organ?]specific diseases such as myopathy or hearing loss, to multisystem disorders with encephalopathy, gastrointestinal dysmotility, and life?]threatening cardiomyopathy. The relationship of the mitochondrion organelle to aging and longevity is also discussed. Laboratory protocols describe methodology to characterize mtDNA heteroplasmy by parallel sequencing. Each eukaryotic cell contains hundreds of mitochondria with hundreds of mitochondria genomes. Mutant and wild-type mtDNA may co-exist as heteroplasmy, and cause human disease. The purpose of this protocol is to simultaneously determine mtDNA sequence and quantify the heteroplasmic level. Another protocol describes procedures for obtaining tissue sections and cell material suitable for histological evaluation of OXPHOS activity and integrity and immunodetection of the complexes in tissue from patients suspected of mitochondrial disease. Emphasis lies on the diagnostic potential of these techniques to differentiate mtDNA from nuclear mutations. This e-book -- a curated collection from eLS, WIREs, and Current Protocols -- offers a fantastic introduction to the field of mitochondrial diseases for students or interdisciplinary collaborators.

Leseprobe

Mitochondrial Diseases

Introduction

Mitochondrial DNA Copy Number Alterations in Human Cancers

Mitochondrial Disorders: Nuclear Gene Mutations

Mitochondria as a Key Determinant of Aging

Advanced Reviews

Mitochondrial tRNA mutations and disease

Human mitochondrial diseases caused by lack of taurine modification in mitochondrial tRNAs

Protocols

Next Generation Sequencing to Characterize Mitochondrial Genomic DNA Heteroplasmy

Histochemical Methods for the Diagnosis of Mitochondrial Diseases

Further Reading

eLS

WIREs

Current Protocols

John Wiley & Sons, Ltd.

eLS subject area: Genetics & Disease

How to cite: Yu, Man (November 2012) Mitochondrial DNA Copy Number Alterations in Human Cancers. In: eLS. John Wiley & Sons, Ltd: Chichester.

DOI: 10.1002/9780470015902.a0024873

Advanced article

Mitochondrial DNA Copy Number Alterations in Human Cancers

Man Yu,Ontario Cancer Institute/Princess Margaret Hospital, University Health Network and University of Toronto, Toronto, Ontario, Canada

Mitochondria are cytoplasmic organelles that participate in adenosine triphosphate (ATP) production through respiration and oxidative phosphorylation (OXPHOS), free radical formation and execution of apoptosis. Perturbation of mitochondrial function has been proposed as one vital hallmark of cancer cells. Besides plenty of germline and polymorphic sequence variations accumulated in both coding and noncoding regions of the mitochondrial genome (mitochondrial deoxyribonucleic acid (DNA); mtDNA), increased or reduced mtDNA copy number has also been increasingly described in a plethora of primary human malignancies. Altered mtDNA quantity may act as an important player in the multistep carcinogenesis of at least some types of human cancer by fuelling tumour initiation and/or advancement. In addition, mtDNA content turnover in bodily liquids from cancer patients could be exploited as a novel molecular tool for early cancer screening and diagnosis.

Key Concepts:

Disruption of mitochondrial function and the oxidative phosphorylation system may lead to cancer occurrence and development.

MtDNA copy number changes have been frequently observed in a wide range of human malignancies.

Aberrant mtDNA quantity is correlated with many key clinicopathological features of cancer patients.

Alterations in mtDNA copy number have potential to affect cancer cell behaviours in vitro and in vivo.

mtDNA content alterations could be considered as a novel biomarker for early cancer detection and diagnosis.

Introduction

Mitochondria are semi-autonomous multifunctional organelles in eukaryotic cells that play indispensable roles in energy metabolism, free radical formation, calcium buffering and apoptosis. Mitochondria carry their own unique genome, namely mitochondrial deoxyribonucleic acid (DNA; mtDNA), which exists in hundreds to thousands of copies in each individual cell and replicates independently of the cell cycle (Clay Montier et al., 2009). Human mtDNA is a ~16.6kb, maternally inherited, closed-circular, double-helical molecule encoding 13 crucial polypeptide subunits of respiratory enzyme complexes, two ribosomal ribonucleic acids (rRNAs) and a set of 22 transfer RNAs required for intramitochondrial protein synthesis (Li et al., 2012). The actual number of mtDNA is dependant on cellular energy demand and may vary substantially between distinct cell types (Clay Montier et al., 2009). mtDNA contains a 1124bp noncoding fragment named displacement (D)-loop with key regulatory elements for controlling mtDNA transcription and duplication (Li , ). Because of limited DNA repair mechanism, the lack of protective histones and its proximity to high concentration of endogenous reactive oxygen species (ROS) generated in the mitochondrial inner membrane, mtDNA is extremely susceptible to oxidative damage and thereby have a much greater mutation rate (10–200 times) than nuclear DNA (nDNA; Cline, ).