Excitotoxicity, calcium and mitochondria: a triad in synaptic neurodegeneration

Abstract

Glutamate is the most commonly engaged neurotransmitter in the mammalian central nervous system, acting to mediate excitatory neurotransmission. However, high levels of glutamatergic input elicit excitotoxicity, contributing to neuronal cell death following acute brain injuries such as stroke and trauma. While excitotoxic cell death has also been implicated in some neurodegenerative disease models, the role of acute apoptotic cell death remains controversial in the setting of chronic neurodegeneration. Nevertheless, it is clear that excitatory synaptic dysregulation contributes to neurodegeneration, as evidenced by protective effects of partial N-methyl-D-aspartate receptor antagonists. Here, we review evidence for sublethal excitatory injuries in relation to neurodegeneration associated with Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis and Huntington's disease. In contrast to classic excitotoxicity, emerging evidence implicates dysregulation of mitochondrial calcium handling in excitatory post-synaptic neurodegeneration. We discuss mechanisms that regulate mitochondrial calcium uptake and release, the impact of LRRK2, PINK1, Parkin, beta-amyloid and glucocerebrosidase on mitochondrial calcium transporters, and the role of autophagic mitochondrial loss in axodendritic shrinkage. Finally, we discuss strategies for normalizing the flux of calcium into and out of the mitochondrial matrix, thereby preventing mitochondrial calcium toxicity and excitotoxic dendritic loss. While the mechanisms that underlie increased uptake or decreased release of mitochondrial calcium vary in different model systems, a common set of strategies to normalize mitochondrial calcium flux can prevent excitatory mitochondrial toxicity and may be neuroprotective in multiple disease contexts.

Keywords: Alzheimer’s disease; Amyotrophic lateral sclerosis; Beta-amyloid; Excitotoxicity; Glucocerebrosidase; Huntington’s disease; LRRK2; Mitochondrial calcium; Mitochondrial calcium uniporter; Mitophagy; NCLX antiporter; PINK1; Parkinson’s disease.

Fig. 1

A combination of factors conspire to promote excitatory mitochondrial toxicity (EMT). (1) Pathophysiological processes linked to neuronal hyperexcitability have been identified in several neurodegenerative disorders. Chronic elevations in cytosolic calcium flux due to neuronal hyperexcitability elicit increased demand for mitochondrial calcium buffering. When hyperexcitability is combined with altered mitochondrial calcium handling and/or other factors that enhance susceptibility to mitochondrial injury, EMT may occur. (2) A set of intrinsic changes in mitochondrial calcium handling are triggered by familial neurodegeneration gene mutations that elicit increased mitochondrial calcium uptake and/or decreased mitochondrial calcium release. Mutations in LRRK2 and SOD1 increase MCU expression, while PINK1 loss-of-function results in decreased phosphorylation and activities of NCLX and LETM1. NCLX is also decreasd in sporadic AD brains and tau inhibits NCLX activity. In some contexts, MCU expression is decreased rather than increased. This has been proposed as a compensatory response, but may still contribute to EMT by exacerbating cytosolic calcium elevations. Alternatively, MCU may be regulated differently in neurons than in glia. (3) Post-synaptic mitochondria are most vulnerable to EMT, and injured mitochondria are removed from dendrites by mitophagy. Elevated mitophagy that is not balanced by mitochondrial replacement results in mitochondrial depletion from dendrites. LOF mutations in the genes encoding PINK1 and Parkin impair mitochondrial biogenesis, while PINK1 mutations and hyperphosphorylation of tau contribute to impaired mitochondrial transport. The resulting loss of mitochondrial support leads to dendritic atrophy, an early sign of neurodegeneration. (4) Many neurodegenerative disease-associated genes also elicit altered calcium handling in other organelles. These alterations, particularly those at the ER-mitochondrial contact sites, may also contribute to dysregulation of cytosolic and/or mitochondrial calcium, although the exact relationships have not been directly addressed. Neurodegenerative disease-linked proteins (genes) include amyloid precursor protein (APP), glucocerebrosidase (GBA), huntingtin (HTT), leucine-rich repeat kinase 2 (LRRK2), Tau (MAPT), PTEN-induced kinase 1 (PINK), presenilin 1 and 2 (PSEN1/2), alpha-synuclein (SNCA) and superoxide dismutase 1 (SOD1). Mut, mutation; LOF, loss-of-function