Mitochondrial Genetics and Cancer

Preface

Contents

Chapter 1: Basic Mitochondrial Genetics, Bioenergetics, and Biogenesis

Introduction

The Mitochondrion

Contrasting Features of Mitochondrial and Nuclear Genetics

Mitochondrial Genomic Structure and Organization

Mitochondrial Microsatellites and D310

Mitochondrial Pseudogenes

The Respiratory Chain

The Electron Transport Chain

Coupling of the Proton Gradient with Oxidative Phosphorylation

The Respiratory Chain and Reactive Oxygen Species Production

Mitochondrial Biogenesis

Mitochondrial Genome Replication

Mitochondrial Genome Transcription

Mitochondrial Transcription Initiation Machinery

Mitochondrial Transcripts

Mitochondrial RNA Processing

Mitochondrial RNA Turnover

Translation of Mitochondrial Messenger RNAs

Control of Mitochondrial Biogenesis

Hormonal Control

Nuclear Respiratory Factors

Peroxisomal Proliferator Activator Receptor Gamma Co-Activator-1a

Regulation of PGC-1

PGC-1a-Related Coactivator

Myc Oncogene and Mitochondrial Biogenesis

Import of Nuclear-Encoded Proteins into Mitochondria

Mitochondrial Import of Cytosolic Transfer RNA

Conclusion

References

Chapter 2: The Warburg Phenomenon and Other Metabolic Alterations of Cancer Cells

Introduction

Bioenergetics of Normal Cells

The Crabtree Effect

The Warburg Phenomenon

Molecular Basis of the Warburg Phenomenon

HK and Glycolysis

The PI3K/AKT Signaling Pathway and Glycolysis

The MYC Oncogene and Glycolysis

Hypoxia-Inducible Factor Pathway and Glycolysis

Regulation of Hypoxia-Inducible Factor

Regulation of Glycolysis and Mitochondrial Functions by Hypoxia-Inducible Factor

P53 and Glycolysis

Glutamine Metabolism in Cancer Cells

Lipid Metabolism in Cancer Cells

Citrate Metabolism by Prostate Glandular Epithelial Cells

Clinical Implications of Altered PCa Metabolism

Diagnostic Imaging of PCa

Screening for PCa Using Biofluids

PCa Prevention and Treatment

Conclusion

References

Chapter 3: Mitochondrial Control of Apoptosis and Cancer

Introduction

Cell Death Processes: The Conundrum of Semantics

Physiologic Importance of Apoptosis

Caspase Cascade

The Intrinsic or Mitochondrial Apoptotic Pathway

Mitochondrial Membrane Permeabilization

BCL-2 Family Members and Regulation of Mitochondrial Membrane Permeabilization

The Execution of Mitochondrial Apoptosis

Viral Control of Mitochondrial Apoptosis

Regulation of Intrinsic Apoptosis by Signaling Pathways

Mitochondrial Fission and Apoptosis

The Extrinsic Apoptotic Pathway

Evasion of Apoptosis by Cancer Cells

Cancer as a Defect in Apoptosis

Intrinsic Apoptotic Pathway Alterations in Cancer

Extrinsic Apoptotic Pathway Alterations in Cancer

Mitochondrial Genetic Defects and Apoptosis

Conclusion

References

Chapter 4: Mitochondrial-to-Nuclear Communications in Cancer

Introduction

Succinate Dehydrogenase and Fumarate Hydratase Mutations and Cancer

SDH Mutations and Cancer

Paragangliomas

Genetics and Clinical Features of PGL

SDH Mutations in Other Cancers

Genetics and Clinical Features of Fumarate Hydratase Mutations

Fumarate Hydratase Mutations in Other Cancers

Genetic Testing and Counseling for SDH and FH Mutations

SDH Mutations

Fumarate Hydratase Mutations

Mechanism of Tumor Induction by SDH and Fumarate Hydratase Mutations

Mitochondria-to-Nuclear Stress Signaling in Cancer

Nuclear Integration of Mitochondrial Genome Fragments and Possible Oncogene Induction

Conclusion

References

Chapter 5: Types of Mitochondrial Genetic Alterations in Cancer

Introduction

Mitochondrial Haplotypes and Haplogroups

Mitochondrial DNA Polymorphisms and Somatic Mutations

Mitochondrial Microsatellites

Discovery of D310 Instability as a Mutational Hot-Spot in Cancer

Mechanism of mtMSI

Clinical Utility of mtMSI

Mitochondrial Genome Rearrangements

Mitochondrial DNA Copy Number (Content) Changes

Novel Mitochondrial Transcripts in Cancer

Pitfalls Associated with Scoring Mitochondrial DNA Mutations

Criticisms of Somatic Mitochondrial DNA Mutations in Cancer

Natural Selection Explains Mitochondrial DNA Mutations in Cancer

Conclusion

References

Chapter 6: Mitochondrial Genetic Alterations in Cancer I

Introduction

Skin Cancer

Melanoma

Nonmelanoma Skin Cancer

Head and Neck Cancer

Salivary Gland Cancer

Thyroid Cancer and Parathyroid Adenoma

Breast Cancer

Lung Cancer

Esophageal Cancer

Gastric Cancer

Colorectal Cancer

Pancreatic Cancer

Hepatocellular Carcinoma

Gallbladder Cancer

Conclusion

References

Chapter 7: Mitochondrial Genetic Alterations in Cancer II

Introduction

Renal Cancer

Bladder Cancer

Prostate Cancer

Ovarian Cancer

Endometrial Cancer

Cervical Cancer

Nervous System Tumors

Hematologic Malignancy

Connective Tissue Cancer

Conclusion

References

Chapter 8: Mitochondrial Genome Rearrangements and Copy Number Changes in Cancer

Introduction

Overview of mtDNA Deletion Disorders

Mitochondrial Genome Deletions in Cancer

Is the CD a Tumor Suppressor?

mtDNA Content Alterations in Cancer

Cancers with Increased mtDNA Content

Cancers with Reduced mtDNA Content

Possible Reasons for mtDNA Repletion or Depletion in Cancer

Increased mtDNA Copy Number

Decreased mtDNA Copy Number

Postulated Mechanisms of Deletion Formation

Control of mtDNA Deletions

Conclusion

References

Chapter 9: Functional Importance of Mitochondrial Genetic Alterations in Cancer

Introduction

Mitochondrial DNA Mutations in Cancer: Cause or Consequence?

Functional Consequences of Mitochondrial DNA Mutations on Mitochondrial Biogenesis in Cancer

Techniques Employed to Study the Contribution of Mitochondrial DNA Mutations in Cancer

Generating rho0 Cells

Producing Transmitochondrial Hybrids (Cybrids)

Nuclear Transfection of Mutant Mitochondrial DNA

Contribution of Mitochondrial DNA Changes to Cancer Biology

Cancer Risk Predisposition

Cancer Initiation

Cancer Cell Proliferation and Growth

Cancer Progression and Metastasis

Acquisition of Hormonal Independence and Chemoresistance by Cancer Cells

Contribution of Mitochondrial Genome Changes to the Development of Oncocytic Tumors

Mitochondrial Membrane Potential and Cancer

Collaborative Evidences from Clinical Studies

Conclusion

References

Chapter 10: The Role of Mitochondrial Reactive Oxygen Species in Cancer

Introduction

ROS Production by Mitochondria

Biomolecular Targets of ROS

Modulation of Intrinsic Apoptosis by ROS

ROS and Hypoxia-Inducible Factor Stabilization in Cancer

ROS and p53 Functions

ROS and Oncogenic Signaling Pathways

MAPK Pathway

PI3K/AKT Pathway

Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B cells Pathway

Activator Protein 1

Protein Kinase C

Myc Oncogene

ROS and Carcinogenesis

Ameliorating the Harmful Effects of ROS

Conclusion

References

Chapter 11: Mitochondrial DNA Measurement in Exfoliated Cells for Cancer Detection and Monitoring: The Copy Number Advantage

Introduction

Tumor Signatures in Biofluids

Mitochondrial Genome Changes in Biofluids of Cancer Patients

Blood (Serum and Plasma)

Salivary Rinses

BAL and Sputum

Nipple Aspirate Fluid and Ductal Lavage

Urine

Cerebrospinal Fluid

Other Biofluids

Exfoliated Skin Cells for Skin Cancer Detection

Clinical Utility of Mitochondrial DNA Changes in Biofluids

Conclusion

References

Chapter 12: Early Cancer Detection and Monitoring Using Changes in the Mitochondrial Genome as Biosensors

Introduction

Field Cancerization Demonstrated by Mitochondrial Genome Changes

Field Cancerization Is a General Carcinogenic Phenomenon: Evidence from Nuclear Genetic Markers

Clinical Importance of Cancer Field Molecular Signatures

Appropriateness of Control Tissue in Cancer Studies

Risk Assessment, Early Cancer Detection, Chemoprevention, and Disease Monitoring

Tumor Margins and Recurrences

Conclusion

References

Chapter 13: Analysis of Mitochondrial Genome Alterations in Cancer

Introduction

Preparation of Clinical Samples for Mitochondrial Genome Analysis in Cancer

Analysis of Mitochondrial Genome Point Mutations in Cancer

Diagnostic Approaches

Restriction Fragment Length Polymorphism

Allele-Specific Oligonucleotide

Single-Strand Conformation Polymorphism Analysis

Heteroduplex Assays

Denaturing High-Performance Liquid Chromatography

Microarray Resequencing of Mitochondrial DNA

DNA Sequencing by Synthesis-(Pyrosequencing)

Analysis of Mitochondrial Genome Deletions and Content Changes

Southern Blotting

Quantitative Polymerase Chase Reaction

Quality Assurance Issues in Mitochondrial DNA Analysis

Conclusion

References

Chapter 14: ``Mitocans´´: Agents Targeting Mitochondria to Kill Cancer Cells

Introduction

Chemotherapy Targets

The Intrinsic Apoptotic Pathway

Agents Targeting Mitochondrial PTPC

Agents Targeting Prosurvival BCL-2 Family Members

Targeting the Mediators of Apoptosis

Targeting Glycolysis to Kill Cancer Cells

Targets of Redox Homeostasis

Targeting Membrane Potential Changes

Cancer Mitochondrial DNA Depletion as a Strategy

Delivery of Toxic Compounds to Mitochondria Using Differential Receptor Expression by Cancer Cells

Conclusion

References

Index