Mitochondrial dysfunction and intracellular calcium dysregulation in ALS

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder that affects the aging population. A progressive loss of motor neurons in the spinal cord and brain leads to muscle paralysis and death. As in other common neurodegenerative diseases, aging-related mitochondrial dysfunction is increasingly being considered among the pathogenic factors. Mitochondria are critical for cell survival: they provide energy to the cell, buffer intracellular calcium, and regulate apoptotic cell death. Whether mitochondrial abnormalities are a trigger or a consequence of the neurodegenerative process and the mechanisms whereby mitochondrial dysfunction contributes to disease are not clear yet. Calcium homeostasis is a major function of mitochondria in neurons, and there is ample evidence that intracellular calcium is dysregulated in ALS. The impact of mitochondrial dysfunction on intracellular calcium homeostasis and its role in motor neuron demise are intriguing issues that warrants in depth discussion. Clearly, unraveling the causal relationship between mitochondrial dysfunction, calcium dysregulation, and neuronal death is critical for the understanding of ALS pathogenesis. In this review, we will outline the current knowledge of various aspects of mitochondrial dysfunction in ALS, with a special emphasis on the role of these abnormalities on intracellular calcium handling.

Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

Figures

Figure 1

Mitochondrial abnormalities in SOD1-fALS. The potential toxic effects of mutant SOD1 to mitochondria (indicated by black jagged symbols) are numerous. See also table 1 for a detailed list of reported mitochondrial abnormalities. Mitochondrial morphological abnormalities, including fragmentation and swelling due to expansion of the IMS, may involve interactions with proteins involved in mitochondrial fusion and fission, protein import, or Bcl proteins. Abnormalities of axonal transport of mitochondria along microtubule axes may result from mutant SOD1 interference with motors and cargo adaptors. Mutant SOD1 accumulation in mitochondria can affect availability of copper necessary for cuproenzymes. Mutant SOD1 in mitochondria can induce excess ROS and NO production. Mitochondrial mutant SOD1 can reduce association of cytochrome c with the IM, and enhance its release thereby activating caspase-dependent cell death. Mutant SOD1 reduces mitochondrial ATP synthesis, respiration, and electron transport chain (ETC) complex activities, especially complex IV. Decreased mitochondrial membrane potential can impair calcium uptake through the mitochondrial uniporter. Mutant SOD1 can causes sensitivity to mPTP opening resulting in release of ions and solutes.

Figure 2

Mechanisms of intracellular calcium homeostasis and signaling. Calcium enters cells from the extracellular space via calcium channels, including store-operated, ligand- and voltage-gated channels. In addition, intracellular calcium rises in response to metabotropic receptor stimulation, for example by glutamate or ATP, and production of IP3, which activates IP3 receptors (IP3R) or ryanodine receptors (not shown in figure) on the ER. IP3R activation induces calcium release from the ER stores, which contain high calcium concentrations because of the activity of SERCA pumps. Calcium is taken up by mitochondria through the membrane potential-dependent activity of the uniporter. Calcium transfer from ER to mitochondria can occur directly through “hotspots” localized on juxtaposed ER/mitochondrial membranes (indicated by dashed ovals). Mitochondrial calcium is extruded by the exchange with sodium by the mitochondrial Na/Ca exchanger. Under mitochondrial permeability transition conditions, stimulated by high calcium and reactive oxygen species (ROS), calcium, along with other solutes, is released through the mPTP. Cytosolic calcium is extruded by the Na/Ca exchanger (NCX) and the plasma membrane calcium ATPase (PMCA).

Figure 3

Involvement of calcium dysregulation in ALS. In the ALS spinal cord, multiple cell types, including MNs and astrocytes, are involved in the disease. The black jagged symbols indicate potential sites of mutant SOD1 toxicity. MNs are particularly vulnerable to increased cytosolic calcium due to low levels of calcium binding proteins and enhanced permeability to calcium through AMPA receptors that contain few GluR2 subunits. Calcium uptake defects mitochondria can cause extended intracellular calcium exposure. In MNs, this may contribute to excitotoxicity, impaired mitochondrial transport, permeability transition, and apoptosis. Mitochondrial bioenergetic dysfunction contributes to increased intracellular calcium, thereby propagating a vicious cycle of calcium dysregulation and cellular damage. Additionally, defective mitochondrial calcium uptake in afferent neurons or astrocytes may result in excessive glutamate release in excitatory synapses. ALS astrocytes have low glutamate transporter (EAAT2) expression, which exacerbates glutamate excitotoxicity. Increased intracellular calcium in astrocytes can also result in excessive propagation of intercellular calcium waves, either through gap junctions or through opening of hemichannels. The resulting extracellular release of modulatory molecules, such as ATP, induces intracellular calcium rise through activation of metabotropic receptors on neighboring cells, and propagates the wave. Furthermore, muscle mitochondrial calcium handling defects can also play a role in muscle degeneration.