Mitochondria in Liver Disease, 1st Edition
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19. Nitric Oxide, Cell Signaling, and Gene Expression, edited by Santiago Lamas
and Enrique Cadenas
20. Resveratrol in Health and Disease, edited by Bharat B. Aggarwal and
Shishir Shishodia
21. Oxidative Stress and Age-Related Neurodegeneration, edited by Yuan Luo
and Lester Packer
22. Molecular Interventions in Lifestyle-Related Diseases, edited by
Midori Hiramatsu, Toshikazu Yoshikawa, and Lester Packer
23. Oxidative Stress and Inflammatory Mechanisms in Obesity, Diabetes, and the
Metabolic Syndrome, edited by Lester Packer and Helmut Sies
24. Lipoic Acid: Energy Production, Antioxidant Activity and Health Effects,
edited by Mulchand S. Patel and Lester Packer
25. Dietary Modulation of Cell Signaling Pathways, edited by Young-Joon Surh,
Zigang Dong, Enrique Cadenas, and Lester Packer
26. Micronutrients and Brain Health, edited by Lester Packer, Helmut Sies,
Manfred Eggersdorfer, and Enrique Cadenas
27. Adipose Tissue and Inflammation, edited by Atif B. Awad and
Peter G. Bradford
28. Herbal Medicine: Biomolecular and Clinical Aspects, Second Edition,
edited by Iris F. F. Benzie and Sissi Wachtel-Galor
29. Inflammation, Lifestyle and Chronic Diseases: The Silent Link,
edited by Bharat B. Aggarwal, Sunil Krishnan, and Sushovan Guha
30. Flavonoids and Related Compounds: Bioavailability and Function,
edited by Jeremy P. E. Spencer and Alan Crozier
31. Mitochondrial Signaling in Health and Disease, edited by Sten Orrenius,
Lester Packer, and Enrique Cadenas
32. Vitamin D: Oxidative Stress, Immunity, and Aging, edited by
Adrian F. Gombart
33. Carotenoids and Vitamin A in Translational Medicine, edited by
Olaf Sommerburg, Werner Siems, and Klaus Kraemer
34. Hormesis in Health and Disease, edited by Suresh I. S. Rattan and
Éric Le Bourg
35. Liver Metabolism and Fatty Liver Disease, edited by Oren Tirosh
36. Nutrition and Epigenetics, edited by Emily Ho and Frederick Domann
37. Lipid Oxidation in Health and Disease, edited by Corinne M. Spickett and
Henry Jay Forman
38. Diversity of Selenium Functions in Health and Disease, edited by
Regina Brigelius-Flohé and Helmut Sies
39. Mitochondria in Liver Disease, edited by Derick Han and Neil Kaplowitz
MITOCHONDRIA IN
LIVER DISEASE
EDITED BY
DERICK HAN
NEIL KAPLOWITZ
CRC Press
Taylor & Francis Group
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Contents
Series Preface.............................................................................................................xi
Preface.................................................................................................................... xiii
Editors....................................................................................................................... xv
Contributors............................................................................................................xvii
Abbreviations........................................................................................................ xxiii
SECTION I Overview of Mitochondria
Chapter 1 Metabolism of Superoxide Radicals and Hydrogen Peroxide
in Mitochondria.....................................................................................3
H. Susana Marinho and Fernando Antunes
Chapter 2 Energy-Redox Axis in Mitochondria: Interconnection of
Energy-Transducing Capacity and Redox Status................................ 29
Zhigang Liu, Harsh Sancheti, Enrique Cadenas, and Fei Yin
Chapter 3 Signal Transduction Pathways That Regulate Mitochondrial
Gene Expression.................................................................................. 45
Chien-Yu Chen, Jingyu Chen, Anketse Debebe, Yang Li, and
Bangyan Stiles
Chapter 4 Transcriptional Regulation of Mitochondrial Biogenesis and
Quality Control................................................................................... 67
Hagir B. Suliman and Claude A. Piantadosi
Chapter 5 Regulation of Liver Mitochondrial Function by
Hydrogen Sulfide.............................................................................. 105
Katalin Módis, Zahra Karimi, and Rui Wang
Chapter 6 The Impact of Aging and Calorie Restriction
on Liver Mitochondria....................................................................... 141
Jon J. Ramsey, José Alberto López-Domínguez,
and Kevork Hagopian
vii
viii Contents
Chapter 7 Drug Delivery to Mitochondria: A Promising Approach for the
Treatment of Liver Disease............................................................... 169
Bhuvaneshwar Vaidya, Samit Shah, and Vivek Gupta
SECTION II The Role of Mitochondria
in Liver Diseases
Chapter 8 The Central Role of Mitochondria in Drug-Induced Liver Injury...... 195
Lily Dara, Heather Johnson, and Neil Kaplowitz
Chapter 9 The Role of Autophagy and Mitophagy in Liver Diseases............... 213
Bilon Khambu, Hao Zhang, and Xiao-Ming Yin
Chapter 10 Mitochondrial Dynamics, Mitophagy and Mitochondrial
Spheroids in Drug-Induced Liver Injury........................................... 237
Jessica A. Williams, Hong-Min Ni, and Wen-Xing Ding
Chapter 11 Biomarkers of Mitochondrial Damage in the Liver.......................... 265
Mitchell R. McGill and Hartmut Jaeschke
Chapter 12 Alterations of Mitochondrial DNA in Liver Diseases...................... 283
Eric A. Schon and Bernard Fromenty
Chapter 13 Epigenetic Modifications of Mitochondrial DNA in Liver
Disease: Focus on Nonalcoholic Fatty Liver Disease....................... 315
Silvia Sookoian and Carlos J. Pirola
Chapter 14 The Emerging Role of Mitochondrial Dynamics in
Viral Hepatitis................................................................................... 327
Seong-Jun Kim, Gulam Syed, Sohail Mohammad,
Mohsin Khan, and Aleem Siddiqui
Chapter 15 Mitochondrial Dynamics and Liver Metabolism.............................. 349
María Isabel Hernández-Alvarez and Antonio Zorzano
Contents ix
Chapter 16 The Role of JNK in Lipotoxicity in the Liver................................... 365
Sanda Win, Tin Aung Than, and Neil Kaplowitz
Chapter 17 Mitochondrial Function, Dysfunction, and Adaptation in the
Liver during the Development of Diabetes....................................... 383
Andras Franko, Martin Hrabê de Angelis, and Rudolf J. Wiesner
Chapter 18 Mitochondrial Dynamics and Adaptation in Alcoholic Liver
Disease and Nonalcoholic Fatty Liver Disease................................. 413
Jerome Garcia, Ho Leung, Bradley Blackshire, Carl Decker,
Christopher Kyaw, and Derick Han
Chapter 19 Acid Sphingomyelinase, Mitochondria, and Liver Diseases............ 433
Carmen Garcia-Ruiz and José C. Fernández-Checa
Chapter 20 Regulation of Liver Metabolism by Sirtuins: Emerging Roles......... 451
Eric S. Goetzman
Series Preface
Oxidative stress is an underlying factor in health and disease. In this series, the sig-
nificance of oxidative stress and disease associated with organ systems is highlighted
by exploring the scientific evidence and the clinical applications of this knowledge.
This series is intended for clinicians and researchers in the basic biomedical sciences.
The potential of such knowledge on healthy aging and disease prevention warrants
further knowledge about how oxidants and antioxidants modulate cell and tissue
function, a theme explored in this book edited by Derick Han and Neil Kaplowitz.
The first section of the book, “Overview of Mitochondria,” consisting of seven
chapters, offers an excellent overview of mitochondria metabolism and their func-
tion in energy-dependent redox reactions, as well as the role of superoxide, hydrogen
peroxide, and hydrogen sulfide in signal transduction and transcription and mito-
chondrial biogenesis. The second section of the book, “The Role of Mitochondria in
Liver Diseases,” focuses on, among other things, the role of mitophagy, epigenetic
mitochondrial DNA modifications, mitochondrial dynamics, and sirtuins in several
liver diseases, such as nonalcoholic fatty liver, viral hepatitis, diabetes, and ceramide
and drug toxicity.
Derick Han and Neil Kaplowitz are congratulated for producing this excellent,
well-organized, and timely book in the expanding field of mitochondrial metabolism
and, especially, how liver energy metabolism—centered on diverse aspects of mito-
chondrial function—is affected by drug toxicity and disease states.
Lester Packer
Enrique Cadenas
xi
Preface
The liver is a vital organ that is responsible for a wide range of functions, most
of which are essential for survival. The multitude of functions the liver performs
makes it vulnerable to a wide range of diseases. The liver is also responsible for
metabolism and clearance of xenobiotic compounds and, thus, is susceptible to
injury caused by drugs, alcohol, and herbal compounds. The liver is a major site for
fatty acid synthesis, thus, is susceptible to developing fatty liver disease. In most of
these diseases, mitochondria appear to play a central role. Mitochondria in Liver
Disease gathers the most current knowledge regarding the role of mitochondria in
liver diseases. This book is divided into two sections. The first section highlights
the latest exciting developments in mitochondrial research. Cutting-edge topics
such as the regulation of mitochondrial respiration by hydrogen sulfide and mito-
chondrial biogenesis are covered. In the second section, the most current research
regarding the role of mitochondria on a wide range of liver diseases are reviewed.
This book, written by experts in the field, provides a comprehensive overview of
the latest research on mitochondria and its central role in mediating liver diseases.
xiii
Editors
Derick Han, PhD, is assistant professor in the Department of Biopharmaceutical
Sciences at the School of Pharmacy, Keck Graduate Institute (Claremont, California),
and a member of The Claremont Colleges. Dr. Han earned his PhD in molecular
pharmacology and toxicology from the School of Pharmacy at the University of
Southern California and a BA in sociology and biochemistry from the University
of California, Berkeley. His research is focused on mitochondrial remodeling in the
liver caused by metabolic stress, such as alcohol. He is also interested in mitochon-
drial reprogramming that occurs in cancer cells. He has published more than 70
research publications, reviews, and book chapters.
Neil Kaplowitz, MD, is director of the University of Southern California–National
Institute of Diabetes and Digestive and Kidney Diseases (USC NIDDK)–sponsored
Research Center for Liver Diseases (Los Angeles, California). He holds two endowed
chairs, the Brem Professor of Medicine and the Budnick Chair in Liver Diseases,
and is chief of the Division of Gastrointestinal and Liver Diseases. He is also profes-
sor of physiology and biophysics and pharmacology and pharmaceutical sciences at
the Keck School of Medicine at the University of Southern California.
Dr. Kaplowitz has received a number of important honors and distinctions,
including election to membership in the American Society for Clinical Investigation
and the Association of American Physicians. He is the recipient of the Western
Gastroenterology Research Prize, the William S. Middleton Award, the Solomon
A. Berson Medical Alumni Achievement Award in Clinical Science from his alma
mater, the Merit Award from the National Institutes of Health, the Mayo Soley Award
from the Western Society for Clinical Investigation, the American Association for
the Study of Liver Diseases (AASLD) Distinguished Achievement Award, and the
American Liver Foundation (ALF) Distinguished Scientific Achievement Award.
He has served as the president of the American Association for the Study of Liver
Diseases and as vice chair for research at the American Liver Foundation. He has
also served as associate editor of leading medical and scientific journals such as
Hepatology, Gastroenterology, and the American Journal of Physiology.
In recent years, he has focused on the role of signal transduction, endoplasmic
reticulum, and mitochondrial stress in the pathogenesis of liver injury. He has pub-
lished more than 195 peer-reviewed scientific articles and 150 scholarly reviews and
has edited 10 books related to liver diseases.
xv
Contributors
Fernando Antunes Lily Dara
Laboratory of Biochemistry of Oxidants Division of Gastrointestinal and Liver
and Antioxidants Diseases
Centre and Department of Chemistry Department of Medicine
and Biochemistry Research Center for Liver Diseases
School of Sciences Keck School of Medicine
University of Lisbon University of Southern California
Lisbon, Portugal Los Angeles, California
Anketse Debebe
Bradley Blackshire Department of Pharmacology and
Department of Biology Pharmaceutical Sciences
University of La Verne School of Pharmacy
La Verne, California University of Southern California
Los Angeles, California
Enrique Cadenas
Carl Decker
Department of Pharmacology and
Department of Biopharmaceutical
Pharmaceutical Sciences
Sciences
School of Pharmacy
School of Pharmacy
University of Southern California
Keck Graduate Institute
Los Angeles, California
Claremont, California
Chien-Yu Chen Wen-Xing Ding
Department of Pharmacology and Department of Pharmacology,
Pharmaceutical Sciences Toxicology, and Therapeutics
School of Pharmacy School of Medicine
University of Southern California University of Kansas, Kansas City
Los Angeles, California Kansas City, Missouri
José C. Fernandez-Checa
Jingyu Chen Liver Unit, Hospital Clinic–IDIBAPS
Department of Pharmacology and Department of Cell Death and
Pharmaceutical Sciences Proliferation
School of Pharmacy Institute of Biomedical Research of
University of Southern California Barcelona
Los Angeles, California Barcelona, Spain
xvii
xviii Contributors
Andras Franko María Isabel Hernández-Alvarez
Institute of Experimental Genetics Department of Biochemistry and
Helmholtz Zentrum München GmbH Molecular Biology
and University of Barcelona
German Center for Diabetes Research and
Neuherberg, Germany Molecular Medicine Program of the
Institute of Research in Biomedicine
Bernard Fromenty IRB Barcelona
INSERM, U991 and
University of Rennes 1 CIBER from Diabetes and Metabolic
Rennes, France Associated Diseases
Health Care Institute Carlos III
Carmen Garcia-Ruiz Barcelona, Spain
Liver Unit, Hospital Clinic–IDIBAPS
Department of Cell Death and Martin Hrabê de Angelis
Proliferation Institute of Experimental Genetics
Institute of Biomedical Research of Helmholtz Zentrum München GmbH
Barcelona and
Barcelona, Spain German Center for Diabetes Research
Neuherberg, Germany
Jerome Garcia
Department of Biology and
University of La Verne WZW–Center of Life and Food
La Verne, California Sciences
Weihenstephan Technische Universität
Eric S. Goetzman München
Division of Medical Genetics Weihenstephan, Germany
Department of Pediatrics
Children’s Hospital of Pittsburgh
University of Pittsburgh Medical Center Hartmut Jaeschke
Pittsburgh, Pennsylvania Department of Pharmacology,
Toxicology, and Therapeutics
School of Medicine
Vivek Gupta
University of Kansas, Kansas City
Department of Biopharmaceutical
Kansas City, Missouri
Sciences
School of Pharmacy
Keck Graduate Institute Heather Johnson
Claremont, California Division of Gastrointestinal and Liver
Diseases
Kevork Hagopian Department of Medicine
Department of Molecular Biosciences Research Center for Liver Diseases
School of Veterinary Medicine Keck School of Medicine
University of California, Davis University of Southern California
Davis, California Los Angeles, California
