Autophagy and Signaling

Esther Wong, Esther Wong

• Publisher: CRC Press
• Year: 2017
• ISBN:
  9781351646970
• Edition: 1
• Topic: Biological Sciences
• Subtopic: Cell Biology
• Index: Biological Sciences

Autophagy and Signaling is an up-to-date overview of the many signaling pathways regulating autophagy in response to different cellular needs. Discussion includes the status and future directions of autophagy signaling research with respect to different aspects of health and disease. These include the roles of autophagy in regulating cell fate, immune response and host defense, nutrient sensing and metabolism, neural functions and homeostasis. The mechanisms and significance of cross-talk between autophagy and other cellular processes is also explored. Lastly, alterations in autophagy observed in aging and age-related pathologies are described.

Section IV

Autophagy in Neural Homeostasis and Neurodegeneration

8 Mitophagy and Neurodegeneration

Kah-Leong Lim

National Neuroscience Institute, Singapore

National University of Singapore, Singapore

Hui-Ying Chan and Grace G.Y. Lim

National Neuroscience Institute, Singapore

Tso-Pang Yao

Duke University School of Medicine, Durham, NC

CONTENTS

8.1 Introduction

8.2 Mitophagy: Past and Present

8.3 Mitophagy in Neurons

8.4 Mitophagy and Neurodegeneration

8.4.1 Mitophagy in Parkinson’s Disease

8.4.2 Mitophagy in Other Neurodegenerative Diseases

8.5 Concluding Remarks

Acknowledgments

References

8.1 INTRODUCTION

Mitochondria, known as the “powerhouse of the cell,” are the principal sites of adenosine triphosphate (ATP) production in aerobic, nonphotosynthetic eukaryotic cells. Most classical textbooks depict these double membrane–bound organelles as solitary and static structures. However, we now know that mitochondria are complex, dynamic, and mobile organelles that constantly undergo membrane remodeling through repeated cycles of fusion and fission, as well as regulated turnover. Collectively, these varied processes help maintain the quality, and thereby the optimal function of mitochondria, as well as allow the organelle to respond rapidly to changes in cellular energy status. The dynamic nature of mitochondria is particularly important for neuronal function, whose unique demands for energy require a highly adaptable mitochondrial network to support. The high energy demand of neurons is critical for several bioenergetically expensive neuronal processes that include axonal transport of macromolecules and organelles (including mitochondria) toward distally located synaptic terminals, maintenance of membrane potential, neurotransmitters uptake and release, and buffering of cytosolic calcium (Schwarz 2013). Among these, perhaps the need for active transportation of components over large distances is one that best distinguishes neurons from their nonneuronal counterparts and arguably also the most fascinating feature about these polarized cells. Although the dimensions of the majority of cells in our body are in the micrometers range, neurons can extend their processes (especially the axon) for much longer distances. For example, the axonal length of a motor neuron in humans is about 1 m. In blue whales, spinal tracts can reach an unimaginable 30 m length (Durcan et al. 2014)! Even when confined to the human brain, the axonal length of projection neurons such as the substantia nigra dopaminergic neurons, including its arborization, can be as long as 0.5 m, and each axon in turn can support nearly 400,000 synapses (Matsuda et al. 2009). The maintenance of an active transport system to supply energy to distally located synapses presents an exquisite challenge to neurons. Furthermore, synapses are themselves metabolically extremely demanding. With every synaptic vesicle release, tens of millions of ions will enter the postsynaptic side as a result of the opening of ion channels. To return the postsynaptic activated neuron to the basal state, one could imagine the large number of ATP that needs to be hydrolyzed to transport the influxed ions out to the extracellular space. The same scenario happens with every action potential fired as the neuronal membrane restores itself back to the resting potential. Notwithstanding this, it is perhaps still amazing to note from a recent imaging study that a single cortical neuron consumes nearly 5 billion ATP per second (Zhu et al. 2012)! One could therefore readily appreciate the urgency for neurons to maintain a constant pool of bioenergetically competent mitochondria that are appropriately distributed to all regions of the cell and to organize these organelles into a dynamic network that could respond rapidly to the changing landscape of neuronal ATP needs. As mentioned above, the remodeling of mitochondrial network also includes its turnover. This is particularly important for postmitotic neurons that need to survive through the entire lifespan of an organism. Comparatively, the lifespan of injured mitochondria is much shortened. Hence, timely removal of these damaged mitochondria is of utmost importance to maintain healthy mitochondrial network to support neuronal survival. The constant turnover of old and/or dysfunctional mitochondria is achieved by a regulated process known as “mitophagy.” Significant insights have been obtained in the last decade or so regarding the process of intracellular mitochondrial clearance. However, much of what we know about the mechanisms underlying mitophagy is gleaned from studies in nonneuronal cells that are usually conducted in the presence of chemical uncouplers such as carbonyl cyanide m-chlorophenylhydrazone (CCCP). These chemicals serve to collapse the mitochondrial membrane potential (ΔΨm), typically at a concentration that is generally regarded as nonphysiological. Nonetheless, the information obtained has been useful in guiding researchers toward the elucidation of a similar mechanism underlying mitophagy in neurons. In the following sections, we will provide a brief overview of the mechanisms underlying mitophagy and an update on the current understandings of the process in neurons along with its potential role in neurodegeneration.

8.2 MITOPHAGY: PAST AND PRESENT

Mitophagy is a process whereby mitochondria are selectively targeted to the lysosomes for degradation via autophagy. This phenomenon usually occurs in the presence of mitochondrial damage as a form of intracellular quality control mechanism to prevent the accumulation of unwanted materials that could compromise cellular functions. Although mitophagy has been a highly researched and studied field in the recent years, the degradation of mitochondria by lysosomes, especially in the presence of cellular starvation, has already been appreciated for more than half a century. In 1962, Ashford and Porter examined liver cells perfused with glucagon by means of electron microscopy and found that the number of mitochondria-enriched lysosomes was dramatically increased in these cells relative to control preparations. In addition, these mitochondria exhibit “varying degree of structural decay” (Ashford and Porter 1962). The term “mitophagy” was however coined more recently by Lemasters (2005), who suggested the presence of selectivity in the process, particularly in reference to a report by Kissova et al. (2004) who demonstrated that Uth1p, a specific outer membrane protein in yeast, is required for efficient mitochondrial autophagy. A series of papers by other groups of researchers around the same time further showed that depolarized mitochondria are selectively targeted for elimination (Elmore et al. 2001; Priault et al. 2005) and that organelle fission is required to segregate dysfunctional mitochondria from the healthy population to permit their specific removal by mitophagy (Twig et al. 2008). However, little was known about the proteins regulating the mitophagy process in mammalian cells although the Bcl-2 homology 3 (BH3)-only family member BCL2/adenovirus E1B 19 kDa protein-interacting protein 3-like (BNIP3L)/NIX was found to promote programmed mitochondrial clearance during reticulocyte maturation (Schweers et al. 2007).

A major breakthrough in the understanding of the molecular mechanisms underlying mitophagy came from the seminal discovery by Richard Youle’s group who found that Parkin, a Parkinson’s disease (PD)-linked ubiquitin ligase, is a key mammalian regulator of the process. Subsequent studies by his group and several others revealed that Parkin collaborates with another PD-linked gene product known as PINK1 (encoding a mitochondrial targeted serine/threonine kinase) to mediate mitophagy (Geisler et al. 2010; Matsuda et al. 2010; Narendra et al. 2010; Vives-Bauza et al. 2010). Collectively, these initial reports triggered an explosion of interest among the global mitochondrial research community in delineating the pathways involved in Parkin/PINK1-mediated mitophagy, with the excitement ensuing to this date. A model that has emerged from these studies is shown in Figure 8.1. Until recently, the model describes a linear sequence of events occurring in response to mitochondrial depolarization that culminates in their removal. According to the proposed model (Youle and Narendra 2011), a key initial event that occurs upon mitochondrial depolarization is the selective accumulation of PINK1 on the outer membrane of the damaged organelle. This accumulation allows PINK1 to recruit Parkin (Okatsu et al. 2012), whose latent ubiquitin ligase activity becomes unmasked along the way in part due to its phosphorylation by PINK1 (Kondapalli et al. 2012; Matsuda et al. 2010). PINK1 also phosphorylates ubiquitin, which binds and activat...

Table of contents

• Title Page
• Copyright Page
• Table of Contents
• Series Preface
• Preface
• Contributors
• Section I: Signaling Pathways Regulating Autophagy
• Section II: Autophagy and Cell Fate
• Section III: Autophagy in Immunity and Metabolism
• Section IV: Autophagy in Neural Homeostasis and Neurodegeneration
• Index