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Title: ARALAR/AGC1 deficiency, a neurodevelopmental disorder with severe impairment of neuronal mitochondrial respiration, does not produce a primary increase in brain lactate.
Authors: Juaristi, Inés
García-Martín, María L
Rodrigues, Tiago B
Satrústegui, Jorgina
Llorente-Folch, Irene
Pardo, Beatriz
Keywords: ARALAR/AGC1 deficiency;lactate;magnetic resonance spectroscopy;malate-aspartate shuttle;mitochondrial aspartate-glutamate carrier;mitochondrial disorders
metadata.dc.subject.mesh: Aggrecans
Amino Acid Transport Systems, Acidic
Brain Chemistry
Glucosephosphate Dehydrogenase
Hereditary Central Nervous System Demyelinating Diseases
Lactic Acid
Mice, Inbred C57BL
Mice, Knockout
Mitochondrial Diseases
Nervous System Diseases
Oxygen Consumption
Psychomotor Disorders
Issue Date: 22-May-2017
Abstract: ARALAR/AGC1 (aspartate-glutamate mitochondrial carrier 1) is an important component of the NADH malate-aspartate shuttle (MAS). AGC1-deficiency is a rare disease causing global cerebral hypomyelination, developmental arrest, hypotonia, and epilepsy (OMIM ID #612949); the aralar-KO mouse recapitulates the major findings in humans. This study was aimed at understanding the impact of ARALAR-deficiency in brain lactate levels as a biomarker. We report that lactate was equally abundant in wild-type and aralar-KO mouse brain in vivo at postnatal day 17. We find that lactate production upon mitochondrial blockade depends on up-regulation of lactate formation in astrocytes rather than in neurons. However, ARALAR-deficiency decreased cell respiration in neurons, not astrocytes, which maintained unchanged respiration and lactate production. As the primary site of ARALAR-deficiency is neuronal, this explains the lack of accumulation of brain lactate in ARALAR-deficiency in humans and mice. On the other hand, we find that the cytosolic and mitochondrial components of the glycerol phosphate shuttle are present in astrocytes with similar activities. This suggests that glycerol phosphate shuttle is the main NADH shuttle in astrocytes and explains the absence of effects of ARALAR-deficiency in these cells.
metadata.dc.identifier.doi: 10.1111/jnc.14047
Appears in Collections:Producción 2020

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