The Mitochondrial Aspartate/Glutamate Carrier AGC1 and Calcium Homeostasis: Physiological Links and Abnormalities in Autism

Abstract

Autism spectrum disorder (ASD) is a severe, complex neurodevelopmental disorder characterized by impairments in reciprocal social interaction and communication, and restricted and stereotyped patterns of interests and behaviors. Recent evidence has unveiled an important role for calcium (Ca(2+)) signaling in the pathogenesis of ASD. Post-mortem studies of autistic brains have pointed toward abnormalities in mitochondrial function as possible downstream consequences of altered Ca(2+) signaling, abnormal synapse formation, and dysreactive immunity. SLC25A12, an ASD susceptibility gene, encodes the Ca(2+)-regulated mitochondrial aspartate-glutamate carrier, isoform 1 (AGC1). AGC1 is an important component of the malate/aspartate shuttle, a crucial system supporting oxidative phosphorylation and adenosine triphosphate (ATP) production. Here, we review the physiological roles of AGC1, its links to calcium homeostasis, and its involvement in autism pathogenesis.

Metabolomics as a Tool for Discovery of Biomarkers of Autism Spectrum Disorder in the Blood Plasma of Children

“…Mutations in the aspartate/glutamate mitochondrial transporter, SLC25A12, have been previously associated with ASD [47]. This transporter is an important component of the malate/aspartate shuttle, a crucial system supporting oxidative phosphorylation, adenosine triphosphate production, and key metabolites for the urea cycle [47].…”

The control of brain mitochondrial energization by cytosolic calcium: The mitochondrial gas pedal

“…In 2004 (102)(103)(104). In contrast, they detected hints of an abnormal functioning of mitochondria due to a permanent activation by excessive elevated Ca 2þ levels.…”

“…In contrast, they detected hints of an abnormal functioning of mitochondria due to a permanent activation by excessive elevated Ca 2þ levels. This led them to the conclusion that mutations in other proteins are probably responsible for the primary Ca 2þ -related dysfunctions resulting in permanently increased Ca 2þ cyt and this secondarily causes a permanent over-energization of mitochondria (102).…”

Neural network modelling of the influence of channelopathies on reflex visual attention

“…Furthermore, the maintenance of calcium homeostasis is crucially important in the functioning of immune cells, 3 and recent studies have revealed evidence of altered Ca 2? homeostasis in ASD (Palmieri et al 2008;Napolioni et al 2011). Together, these studies point towards a causal link from channel-mediated intracellular calcium imbalance in autism and the disturbed neurodevelopment of autistic subjects.…”

“…Dysregulated calcium homeostasis has been observed at the macro level by Palmieri et al (2008). This finding of dysregulated homeostasis was later linked with calcium signalling defects by Napolioni et al (2011). It is known that voltage-gated calcium channels are essential to neuronal maturation and differentiation, in addition to their central function in neural information processing (McEnery et al 1998).…”