AUTHOR=Verma Manish , Wills Zachary , Chu Charleen T. 

TITLE=Excitatory Dendritic Mitochondrial Calcium Toxicity: Implications for Parkinson’s and Other Neurodegenerative Diseases

JOURNAL=Frontiers in Neuroscience

VOLUME=Volume 12 - 2018

YEAR=2018

URL=https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2018.00523

DOI=10.3389/fnins.2018.00523

ISSN=1662-453X

ABSTRACT=Dysregulation of calcium homeostasis has been linked to multiple neurological
diseases. In addition to excitotoxic neuronal cell death observed following stroke, a
growing number of studies implicate excess excitatory neuronal activity in chronic
neurodegenerative diseases. Mitochondria function to rapidly sequester large influxes of
cytosolic calcium through the activity of the mitochondrial calcium uniporter (MCU)
complex, followed by more gradual release via calcium antiporters such as NCLX. Increased
cytosolic calcium levels almost invariably result in increased mitochondrial calcium uptake.
While this compensatory response may limit classic excitotoxic injury in the short term,
recent studies employing live calcium imaging and molecular manipulation of calcium
transporter activities suggest that mitochondrial calcium overload plays a key role in
Parkinson’s disease (PD), Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS)
and related dementias (PDD, DLB, FTD). Herein, we review the literature on increased
excitatory input, mitochondrial calcium dysregulation, and the transcriptional or posttranslational
regulation of mitochondrial calcium transport proteins, with an emphasis on
the PD-linked kinases LRRK2 and PINK1. The neuroprotective effects of modulating MCU,
NCLX and LETM1 are reviewed. We propose that the shortening and simplification of the
dendritic arbor observed in neurodegenerative diseases occur through excitatory
mitochondrial toxicity (EMT), which triggers mitophagy and perisynaptic mitochondrial
depletion, mechanisms that are distinct from classic excitotoxicity.