The Functions, Disease-Related Dysfunctions, and Therapeutic Targeting of Neuronal Mitochondria

J. Marie Hardwick, Valentin K. Gribkoff, Elizabeth A. Jonas, Valentin K. Gribkoff, Elizabeth A. Jonas

• Publisher: Wiley
• Year: 2015
• Print ISBN: 9781118709238
• eBook ISBN: 9781119017103
• Edition: 1
• Topic: Sciences biologiques
• Subtopic: Pharmacologie

This book presents advances in the field of neuronal mitochondria – functions, relation to therapeutics, and pharmacology. For scientists and researchers in both industry and academia, this book provides detailed discussion, examples, and approaches, to illustrate the potential of mitochondria as therapeutic targets for neuronal diseases. • Helps readers understand the regulation of mitochondrial cellular processes, such as substrate metabolism, energy production, and programmed versus sporadic cell death
• Offers insights on the development of strategies for targeted therapeutic approaches and potential personalized treatments
• Includes examples of mitochondrial drugs, development, and mitochondria-targeted approaches for more efficient treatment methods and further developments in the field
• Covers the model systems and approaches needed for the development of new drugs for the central nervous system to provide potential modern therapeutics for neurodegenerative disorders

SECTION II
CONTROL OF MITOCHONDRIAL SIGNALING NETWORKS

4
MITOCHONDRIAL Ca2+ TRANSPORT IN THE CONTROL OF NEURONAL FUNCTIONS: MOLECULAR AND CELLULAR MECHANISMS

Yuriy M. Usachev

Department of Pharmacology, University of Iowa College of Medicine, Iowa City, Iowa

4.1 INTRODUCTION

The ability of mitochondria to transport Ca²⁺ has been recognized for several decades (Carafoli, 2003; Carafoli and Lehninger, 1971; Deluca and Engstrom, 1961; Drago, Pizzo, and Pozzan, 2011; Vasington and Murphy, 1962). The fact that mitochondrial Ca²⁺ transport remains a focus of intensive investigation to this day reflects the importance of this process in the control of many determinants of cell life and death (Babcock and Hille, 1998; Friel, 2000; Newmeyer and Ferguson-Miller, 2003; Nicholls and Budd, 2000; Orrenius, Zhivotovsky, and Nicotera, 2003; Pozzan and Rizzuto, 2000; Thayer et al., 2002) (Fig. 4.1). In neurons, mitochondria efficiently buffer Ca²⁺ influx during excitation, limiting the amplitude of the Ca²⁺ signal. Rapid Ca²⁺ buffering by mitochondria is followed by a much slower Ca²⁺ release back to the cytosol (Bernardi, 1999; Nicholls, 2005; Thayer, Usachev, and Pottorf, 2002), and such Ca²⁺ cycling across the inner mitochondrial membrane markedly prolongs the cytosolic Ca²⁺ response by producing a so-called [Ca²⁺]_i plateau (Figs. 4.1 and 4.2). This phenomenon occurs both in central (Medler and Gleason, 2002; White and Reynolds, 1996) and peripheral (Colegrove, Albrecht, and Friel, 2000a; Dedov and Roufogalis, 2000; Friel and Tsien, 1994; Shishkin et al., 2002; Thayer and Miller, 1990) neurons but is more pronounced in the latter.

FIGURE 4.1 Mitochondrial Ca²⁺ signaling in neurons. Ca²⁺ entering neurons via voltage-gated Ca²⁺ channels (VGCC), glutamate NMDA receptors (NMDA-R), or other Ca²⁺-permeable channels (e.g., TRP channels) is rapidly taken up by mitochondria. This Ca²⁺ uptake is mediated by the mitochondrial Ca²⁺ uniporter. Within mitochondria, Ca²⁺ stimulates ATP synthesis through activation of several Ca²⁺-activated dehydrogenases (Denton, 2009; Glancy and Balaban, 2012). Free Ca²⁺ within the matrix is buffered into Ca-phosphate complexes. Ca²⁺ is released from mitochondria back into the cytosol via at least three mechanisms, Na⁺/Ca²⁺ exchanger, H⁺/Ca²⁺ exchanger, and mitochondrial permeability transition pore (mPTP). Under physiological conditions, Ca²⁺ mobilization from mitochondria is mediated primarily by the mitochondrial Na⁺/Ca²⁺ exchanger. The Ca²⁺ released from mitochondria is ultimately extruded from neurons via the plasma membrane Ca²⁺-ATPases (PMCA) and Na⁺/Ca²⁺ exchangers (NCX). Ca²⁺ uptake and release by mitochondria reduces the amplitude of increase in cytosolic Ca²⁺ concentration ([Ca²⁺]_i), and prolongs the duration of [Ca²⁺]_i elevation. By shaping [Ca²⁺]_i, mitochondrial Ca²⁺ cycling modulates activity of many neuronal Ca²⁺ targets and influences numerous Ca²⁺-dependent functions such as excitability, synaptic transmission, and gene regulation. Under pathological conditions, mitochondrial overload with Ca²⁺ triggers opening of the mPTP, a large channel permeable for Ca²⁺ and small proteins including the pro-apoptotic factors cytochrome c and apoptosis-inducing factor (AIF). Opening of the mPTP triggers a cascade of toxic events (e.g., mitochondrial depolarization, collapse of ATP synthesis, increase in reactive oxygen species (ROS) production, Ca²⁺ deregulation, activation of caspases, and the Ca²⁺-dependent protease calpain), ultimately leading to neuronal demise. The deregulation of mitochondrial Ca²⁺ handling is implicated in neuronal toxicity in stroke, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis (ALS), and other neurodegenerative disorders (Bezprozvanny, 2009; Mattson, Gleichmann, and Cheng, 2008; Pivovarova and Andrews, 2010).

FIGURE 4.2 Mitochondrial Ca²⁺ cycling regulates amplitude and duration of [Ca²⁺]_i responses in neurons. Changes in cytosolic Ca²⁺ concentration ([Ca²⁺]_i) were studied in cultured dorsal root ganglion (DRG) sensory neurons using the Ca²⁺-sensitive indicator Fura-2 as previously described (Kim and Usachev, 2009; Kim et al., 2014; Schnizler et al., 2008; Usachev et al., 2002). a, Superimposition of [Ca²⁺]_i responses to the TRPV1 agonist capsaicin (1 μM; 30 s) recorded in control (black) or in the presence of the electron transport inhibitor antimycin (1 μM) and ATP-synthase inhibitor oligomycin (2 μM) (grey trace). Both traces were obtained from the same cell. Inhibition of mitochondrial Ca²⁺ transport by the antimycin with oligomycin treatment increased the amplitude and reduced the duration of capsaicin-evoked [Ca²⁺]_i elevation (compare grey and black traces). b, [Ca²⁺]_i transients were evoked by trains of action potentials (8 Hz; arrows) of increased duration using extracellular field stimulation. The number of action potentials is shown under the traces. Increasing the strength of the stimulation led to a gradual appearance and prolongation of the [Ca²⁺]_i plateau phase mediated by Ca²⁺ release from mitochondria.

Ca²⁺ transported into the mitochondrial matrix stimulates Ca²⁺-dependent dehydrogenases and boosts ATP production to meet increased energy demand during excitation (Denton, 2009; Glancy and Balaban, 2012; Hajnoczky et al., 1995). However, excessive load of mitochondria with Ca²⁺ triggers neurotoxic processes in stroke and in Alzheimer’s, Parkinson’s, and Huntington’s diseases (Bezprozvanny, 2009; Moskowitz, Lo, and Iadecola, 2010; Murphy, Fiskum, and Beal, 1999; Nicholls and Budd, 2000; Panov et al., 2002; Reynolds, 1999). In addition, mitochondrial-dependent alteration of the amplitude and duration of cytosolic Ca²⁺ signals influences the activation and function of numerous cytosolic Ca²⁺ targets, including Ca²⁺-activated ion channels (e.g., small- and large-conductance Ca²⁺-activated K⁺ channels, SK and BK), Ca²⁺ sensors at the synapse (e.g., synaptotagmins and Doc2) and numerous Ca²⁺-dependent enzymes (e.g., calmodulin-dependent protein kinases, protein kinases A and C, protein phosphatase 2B/calcineurin, and the Ca²⁺-dependent protease calpain) (Berridge, Bootman, and Lipp, 1998; Clapham, 2007; Groffen et al., 2010; Kim and Usachev, 2009; Sah, 1996; Sugita et al., 2002; Xu, Mashimo, and Sudhof, 2007; Yao et al., 2011). Accordingly, mitochondrial Ca²⁺ transport regulates many Ca²⁺-dependent functions including neuronal excitability, synaptic transmission, gene expression, and neuronal survival (see Fig. 4.1).

The fact that mitochondrial Ca²⁺ signaling is key to controlling neuronal life and death makes the components of mitochondrial Ca²⁺ transport attractive candidates for therapeutic targeting in the treatment of neurodegenerative and psychiatric disorders. Although progress in this area was long hindered by a lack of information on the identities of the molecules that mediate Ca²⁺ transport in and out of mitochondria, the recent discovery of several genes encoding key mitochondrial Ca²⁺ transporters (Marchi and Pinton, 2014; Pendin, Greotti, and Pozzan, 2014) is expected to accelerate our progress toward understanding and therapeutically exploiting this machinery.

In this chapter I will review recent advancements in the molecular biology of mitochondrial Ca²⁺ signaling in neurons and discuss how Ca²⁺ transport into and out of neuronal mitochondria contributes to the control of neuron excitability, synaptic transmission, and gene expression (see Fig. 4.1). The role of mitochondrial Ca²⁺ overload in neuronal toxicity, which is another important aspect of mitochondrial Ca²⁺ transport in neurons, is reviewed in the contribution by Brustovetsky (see Chapter 1).

4.2 PHYSIOLOGICAL AND PHARMACOLOGICAL CHARACTERISTICS OF MITOCHONDRIAL Ca²⁺ TRANSPORT IN NEURONS

In neurons at rest, total Ca²⁺ concentration in the matrix ([Ca]_mt) is low, usually <100 nM (Pivovarova et al., 1999; Stanika et al., 2012). During electrical or synaptic stimulation, [Ca]_mt can increase to millimolar levels within seconds (Pivovarova et al., 1999, 2002). In the case of modest to strong stimulation, the rate of mitochondrial Ca²⁺ uptake in intact neur...

Table of contents

• COVER
• TITLE PAGE
• TABLE OF CONTENTS
• CONTRIBUTORS
• PREFACE
• SECTION I: MITOCHONDRIAL STRUCTURE AND ION CHANNELS
• SECTION II: CONTROL OF MITOCHONDRIAL SIGNALING NETWORKS
• SECTION III: DEFECTIVE MITOCHONDRIAL DYNAMICS AND MITOPHAGY
• SECTION IV: MITOCHONDRIA-TARGETED THERAPEUTICS AND MODEL SYSTEMS
• INDEX
• END USER LICENSE AGREEMENT