Preface

This is the fourth volume of the series discussing almost all aspects of the autophagy machinery. This volume presents detailed information on the role of mitophagy in health and disease. The most important function of mitochondria is to supply a large amount of energy required for normal cellular activities. This organelle is also involved in a large number of other essential cellular functions, including thermogenesis, iron-sulfur cluster biogenesis, biosynthesis of heme and certain lipids and amino acids, autophagy, apoptosis, immune response, cell death, cellular homeostasis and metabolism, differentiation, aging, and the production of reactive oxygen species (ROS). Therefore, the maintenance of a healthy pool of mitochondria is vital for normal cellular physiology and survival. On the other hand, mitochondrial dysfunction can have severe consequences including aging and pathogenesis of neurodegenerative diseases. In this respect, Parkinson’s disease, skeletal muscle atrophy, and cardiovascular disease are discussed here. Various steps involved in mitophagy are detailed, and molecular mechanisms underlying this autophagic machinery are reviewed both in yeast and metazoa. Inclusion of information on autophagy including mitophagy in yeast in this volume is relevant and important because studies of yeast have clarified the fundamental principles of autophagy, which serve as a guide for studies of autophagy in metazoans. Almost all aspects of yeast mitophagy, including proteins involved, generation of reactive oxygen species (ROS), and various mechanisms of mitochondrial quality control, are discussed in detail.

As mentioned above, maintaining a healthy and functional population of mitochondria is critically important for all eukaryotic cells. Several quality control systems exist within mitochondria, and an important link between mitochondria maintenance and macroautophagy (mitophagy) has been established. Mitophagy is one of the primary mechanisms for mitochondrial quality control and serves to selectively eliminate dysfunctional or excess mitochondria via an autophagic process that is tightly regulated. The failure to maintain adequate mitophagy leads to accumulation of dysfunctional mitochondria within cells, resulting in cellular dysfunction. Diseases associated with impaired mitophagy include neurodegenerative diseases, myopathies, obesity, and diabetes, most of which are discussed in this volume. The recent advances in our understanding of mitophagy will provide essential insights into the pathogenesis of a variety of mitochondria dysfunction-related diseases.

Several reviews presenting the current understanding of the molecular mechanisms of autophagy involved in cancer, neurodegeneration, aging, infection, and inflammation are included in this volume. At the molecular level, a large group of proteins has been identified in various model organisms which mediate the association of damaged or dysfunctional mitochondria with the autophagic machinery. Four mammalian mitochondrial proteins (tags) (Nix, PINK1, Bnip3, and FUNDC1) are discussed; also the role of Atg32 protein in yeast is explained. PINK1 (encoded by the PARK6 gene) and Parkin (encoded by the PARK2 gene) proteins have provided the most important insight into the mechanism of autophagy in mammalian cells.

PINK1/Parkin mutants (Drosophila) show severe developmental abnormalities associated with mitochondrial dysfunction. In humans, mutations of PINK1 or Parkin are responsible for most cases of early-onset Parkinson’s disease. In healthy mitochondria, PINK1 is imported into mitochondrial inner membrane where it is subsequently degraded by PARL, but in mitochondria with disrupted membrane potential, it is retained on the mitochondrial outer membrane where it recruits Parkin from the cytosol. Once recruited, Parkin initiates mitophagy to eliminate dysfunctional mitochondria. The molecular events involved in PINK1/Parkin promotion of mitophagy are detailed in two chapters.

The role of transmembrane protein Atg32 in autophagy is explained in this volume. Phosphorylated Atg32 is an important mitochondrial tag located in the mitochondrial outer membrane. Phosphorylation of Atg32 is required for recruiting the scaffold protein Atg11, resulting in targeting mitochondria for degradation. Independent of Atg11 binding, Atg8 is recruited to Atg32. Atg8 is essential for autophagosome assembly. Atg11 is also required for other types of autophagies. In fact, the formation of a tripartite (Atg32/Atg11/Atg8) initiator complex is common. Casein kinase 2 is essential for the activation of Atg32.

Another example discussed in this volume is the critical role of Nix and related Bnip3 in mitochondrial autophagy. Nix is located in the mitochondrial outer membrane. The transmembrane domain, but not the BH3 domain of Nix, is essential for its activity. Nix is not required for autophagosome formation, but is essential for sequestration of mitochondria into autophagosomes. Nix plays a vital role in the maturation of the reticulocyte to erythrocyte, during which mitochondria are eliminated by mitophagy.

FUNDC1 is a less known protein located in the mitochondrial outer membrane, with structural similarity to Atg32. Hypoxia induces FUNDC1-dependent mitophagy. Mitochondrial fragmentation accompanies FUNDC1-dependent mitophagy. The role of FUNDC1-dependent mitophagy in hypoxic cancer cells is discussed here.

An interesting example of the role of mitophagy is in mammalian reproduction. Mitophagy occurs physiologically during the removal of sperm mitochondria from egg cells upon fertilization; this process is called allophagy. One possible explanation for such selective mitophagy is that paternal mitochondria are heavily damaged by ROS prior to fertilization, and need to be removed to prevent potentially deleterious effects in the next generation.

It is known that the relentless loss of dopaminergic neurons in the midbrain causes Parkinson’s disease. Mitochondrial and lysosomal functions decrease with age and, therefore, both are implicated in aging and age-related disorders such as Parkinson’s disease. That impaired mitochondrial function is a predominant feature of this disease is explained in this volume. Two specific processes, mitochondrial fission and mitophagy, involved in this disease are described; the former occurs as an early step during neurodegeneration.

As indicated previously, two Parkinson’s disease-associated genes, PINK1 and Parkin, are involved in the maintenance of healthy mitochondria. The pivotal role played by Parkin in maintaining dopaminergic neuronal survival is underscored here, and its dysfunction represents a cause of Parkinson’s disease. Parkin in cooperation with PINK1 specifically recognizes damaged mitochondria, isolates them from the mitochondrial network, and eliminates them through the ubiquitin-proteasome and mitophagy pathways. It is emphasized that PINK1 and Parkin protein identify and segregate damaged mitochondria for degradation by mitophagy via ubiquitination of several mitochondrial proteins including mitofusins. Mutations of PARK2 gene (encoding the ubiquitin ligase Parkin) cause not only familial parkinsonism but also a sporadic form of this disease. As stated before, Parkin is a key regulator of mitochondrial quality control. However, presently the model of Parkin-mediated mitophagy is being debated, which is updated in this volume. The understanding of the molecular mechanisms of PINK1 and Parkin-mediated mitochondrial regulation is also reviewed here.

Intrinsic aging of the cardiovascular system, in addition to chronic exposure to cardiovascular risk factors, is inevitable. This results in the development of cardiovascular disease later in life. It is pointed out that the impairment in mitochondrial function arising from failure of mitochondrial quality control is a major contributing factor to heart senescence. It is also pointed out that damaged mitochondria produce increased amounts of ROS, resulting in oxidative damage to cardiomyocyte components.

Loss of muscle mass and function results mostly from accelerated protein degradation by the ubiquitin-proteasome system and autophagy-lysosome systems. The signaling mechanism underlying the increased protein degradation during muscle atrophy from a genetic perspective is explained here. The importance of mitophagy during skeletal muscle atrophy is pointed out.

The text is divided into three subheadings (General Applications, Molecular Mechanisms, and Role in Disease) for the convenience of the readers.

By bringing together a large number of experts (oncologists, physicians, medical research scientists, and pathologists) in the field of mitophagy, it is my hope that substantial progress will be made against terrible diseases afflicting humans. It is difficult for a single author to discuss effectively and comprehensively various aspects of an exceedingly complex process such as mitophagy. Another advantage of involving more than one author is to present different points of view on various controversial aspects of the role of mitophagy in health and disease. I hope these goals will be fulfilled in this and future volumes of this series.

This volume was written by 39 contributors representing 9 countries. I am grateful to them for their promptness in accepting my suggestions. Their practical experience highlights the very high quality of their writings, which should build and further the endeavors of the readers in this important medical field. I respect and appreciate the hard work and exceptional insight into the mitophagy machinery provided by these contributors.

It is my hope that subsequent...