About
190
Publications
21,047
Reads
How we measure 'reads'
A 'read' is counted each time someone views a publication summary (such as the title, abstract, and list of authors), clicks on a figure, or views or downloads the full-text. Learn more
7,716
Citations
Introduction
Additional affiliations
January 2006 - present
Publications
Publications (190)
![Scheme of the cerebral metabolism of [1,2‐¹³C2]glucose,...](publication/370692389/figure/fig5/AS:11431281244777202@1716007851559/Scheme-of-the-cerebral-metabolism-of-1-2-C2glucose-U-C3-hydroxybutyrate-and_Q320.jpg)
Sebastián Cerdán, a wonderful colleague and brilliant and innovative NMR spectroscopist sadly passed away in May 2022. His studies using multinuclear magnetic resonance spectroscopy (MRS) techniques contributed greatly to the understanding of brain metabolism, including identification of the pyruvate recycling pathway in brain and determining metab...
The deficiency of CITRIN, the liver mitochondrial aspartate-glutamate carrier (AGC), is the cause of four human clinical phenotypes, neonatal intrahepatic cholestasis caused by CITRIN deficiency (NICCD), silent period, failure to thrive and dyslipidemia caused by CITRIN deficiency (FTTDCD), and citrullinemia type II (CTLN2). Clinical symptoms can b...
Calcium is a major regulator of cellular metabolism. Calcium controls mitochondrial respiration, and calcium signaling is used to meet cellular energetic demands through energy production in the organelle. Although it has been widely assumed that Ca2+-actions require its uptake by mitochondrial calcium uniporter (MCU), alternative pathways modulate...
Aralar/AGC1/Slc25a12, the mitochondrial aspartate-glutamate carrier expressed in neurons, is the regulatory component of the NADH malate-aspartate shuttle. AGC1 deficiency is a neuropediatric rare disease (OMIM #612949, also named early infantile epileptic encephalopathy 39) characterized by hypomyelination, hypotonia, developmental arrest and epil...
Introduction: The regulation of adenine nucleotide levels in the mitochondria and the cytosol is essential for cell metabolism. To sustain mitochondrial respiration, ATP generated by ATP synthase must be exported to the cytosol, whereas mitochondria must be refilled with ADP and Pi. Adenine Nucleotide Translocases (ANTs), which catalyze the electro...
Calcium is an important second messenger regulating a bioenergetic response to the workloads triggered by neuronal activation. In embryonic mouse cortical neurons using glucose as only fuel, activation by NMDA elicits a strong workload (ATP demand) dependent on Na+ and Ca2+ entry, and stimulates glucose uptake, glycolysis, pyruvate and lactate prod...
AGC1/Aralar/Slc25a12 is the mitochondrial carrier of aspartate-glutamate, the regulatory component of the NADH malate-aspartate shuttle (MAS) that transfers cytosolic redox power to neuronal mitochondria. The deficiency in AGC1/Aralar leads to the human rare disease named “early infantile epileptic encephalopathy 39” (EIEE 39, OMIM # 612949) charac...
Charcot–Marie-Tooth (CMT) disease is a neuropathy that lacks effective therapy. CMT patients show degeneration of peripheral nerves, leading to muscle weakness and loss of proprioception. Loss of mitochondrial oxidative phosphorylation proteins and enzymes of the antioxidant response accompany degeneration of nerves in skin biopsies of CMT patients...
Calcium is an important second messenger regulating a bioenergetic response to the workloads triggered by neuronal activation. In cortical neurons using glucose as only fuel, activation by NMDA, which elicits a strong workload dependent on Na+ entry, stimulates glucose uptake, glycolysis, pyruvate and lactate production, and OXPHOS in a Ca2+-depend...
Ganglioside-induced differentiation associated protein 1 (GDAP1) gene encodes a protein of the mitochondrial outer membrane and of the mitochondrial membrane contacts with the endoplasmic reticulum (MAMs) and lysosomes. Since mutations in GDAP1 cause Charcot–Marie–Tooth, an inherited motor and sensory neuropathy, its function is essential for perip...
Aralar/AGC1/Slc25a12, the mitochondrial aspartate-glutamate carrier expressed in neurons, is the regulatory component of the NADH malate-aspartate shuttle. AGC1 deficiency is a neuropediatric rare disease characterized by hypomyelination, hypotonia, developmental arrest, and epilepsy. We have investigated whether β-hydroxybutyrate (βOHB), the main...
The brain uses mainly glucose as fuel with an index of glucose to oxygen utilization close to 6, the maximal index if all glucose was completely oxidized. However, this high oxidative index, contrasts with the metabolic traits of the major cell types in the brain studied in culture, neurons and astrocytes, including the selective use of the malate-...
The elevated energy demands in the brain are fulfilled mainly by glucose catabolism. In highly polarized neurons, about 10-50% of mitochondria are transported along microtubules using mitochondrial-born ATP to locations with high energy requirements. In this report, we have investigated the impact of Aralar deficiency on mitochondrial transport in...
The pathology of Charcot-Marie-Tooth (CMT), a disease arising from mutations in different genes, has been associated with an impairment of mitochondrial dynamics and axonal biology of mitochondria. Mutations in ganglioside-induced differentiation-associated protein 1 (GDAP1) cause several forms of CMT neuropathy, but the pathogenic mechanisms invol...
Astrocytes respond to energetic demands by upregulating glycolysis, lactate production, and respiration. This study addresses the role of respiration and calcium regulation of respiration as part of the astrocyte response to the workloads caused by extracellular ATP and glutamate. Extracellular ATP (100 μM to 1 mM) causes a Ca²⁺‐dependent workload...
Purpose:
MDH2 (malate dehydrogenase 2) has recently been proposed as a novel potential pheochromocytoma/paraganglioma (PPGL) susceptibility gene, but its role in the disease has not been addressed. This study aimed to determine the prevalence of MDH2 pathogenic variants among PPGL patients and determine the associated phenotype.
Methods:
Eight h...
Neurodegenerative diseases are a spectrum of chronic, debilitating disorders characterised by the progressive degeneration and death of neurons. Mitochondrial dysfunction has been implicated in most neurodegenerative diseases, but in many instances it is unclear whether such dysfunction is a cause or an effect of the underlying pathology, and wheth...
Store-operated calcium entry (SOCE) is a Calcium (Ca2+) influx pathway activated by depletion of intracellular stores that occurs in eukaryotic cells. In neurons, the presence and functions of SOCE are still in question. Here, we show evidences for the existence of SOCE in primary mouse cortical neurons. Endoplasmic reticulum (ER)-Ca2+ depletion us...
Neurodegenerative diseases are a spectrum of chronic, debilitating disorders characterised by the progressive degeneration and death of neurons. Mitochondrial dysfunction has been implicated in most neurodegenerative diseases, but in many instances it is unclear whether such dysfunction is a cause or an effect of the underlying pathology, and wheth...
A series of simplex cases have been reported under various diagnoses sharing early aging, especially evident in congenitally decreased subcutaneous fat tissue and sparse hair, bone dysplasia of the skull and fingers, a distinctive facial gestalt, and prenatal and postnatal growth retardation. For historical reasons, we suggest naming the entity Fon...
A micro-sampling and straightforward method based on high resolution continuum source atomic absorption spectrometry (HR-CS AAS) was developed to determine extracellular and intracellular Ca in samples of interest in clinical and biomedical analysis. Solid sampling platforms were used to introduce the micro-samples into the graphite furnace atomize...
Purpose: Mutations in Krebs cycle genes are frequently found in patients with pheochromocytomas/paragangliomas. Disruption of SDH, FH or MDH2 enzymatic activities lead to accumulation of specific metabolites, which give rise to epigenetic changes in the genome that cause a characteristic hypermethylated phenotype. Tumors showing this phenotype, but...
ARALAR / AGC 1 (aspartate‐glutamate mitochondrial carrier 1) is an important component of the NADH malate‐aspartate shuttle ( MAS ). AGC 1‐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 stud...
GDAP1 is an outer mitochondrial membrane protein involved in Charcot-Marie-Tooth (CMT) disease. Lack of GDAP1 gives rise to altered mitochondrial networks and endoplasmic reticulum (ER)-mitochondrial interactions resulting in a decreased ER-Ca2+ levels along with a defect on store-operated calcium entry (SOCE) related to a misallocation of mitochon...
The mitochondrial aspartate/glutamate transporter Aralar/AGC1/Slc25a12 is critically involved in brain aspartate synthesis, and AGC1 deficiency results in a drastic fall of brain aspartate levels in humans and mice. It has recently been described that the uncoupling protein UCP2 transports four carbon metabolites including aspartate. Since UCP2 is...
Abstract
Purpose: To characterize the vision phenotype of mice lacking Aralar/AGC1/Slc25a12, the mitochondrial aspartate-glutamate carrier mutated in global cerebral hypomyelination (OMIM 612949).
Methods: We tested overnight dark-adapted control and aralar-deficient mice for the standard full electroretinogram (ERG) response. The metabolic stres...
Niemann-Pick disease type A (NPA) is a rare lysosomal storage disorder characterized by severe neurological alterations that leads to death in childhood. Loss-of-function mutations in the acid sphingomyelinase (ASM) gene cause NPA, and result in the accumulation of sphingomyelin (SM) in lysosomes and plasma membrane of neurons. Using ASM knockout (...
Aims:
A loss in brain acetylcholine and cholinergic markers, subchronic inflammation, and impaired mitochondrial function, which leads to low energy production and high oxidative stress, are common pathological factors in several neurodegenerative diseases. Glial cells are important for brain homeostasis and microglia controls the central immune r...
ARALAR/AGC1/Slc25a12, the aspartate-glutamate carrier from brain mitochondria, is the regulatory step in the malate-aspartate NADH shuttle, MAS. MAS is used to oxidize cytosolic NADH in mitochondria, a process required to maintain oxidative glucose utilization. The role of ARALAR was analyzed in two paradigms of glutamate-induced excitotoxicity in...
Mitochondrial function is regulated by calcium. In addition to the long known effects of matrix Ca(2+), regulation of metabolite transport by extramitochondrial Ca(2+) represents an alternative Ca(2+)-dependent mechanism to regulate mitochondrial function. The Ca(2+) regulated mitochondrial transporters (CaMCs) are well suited for that role, as the...
Production of energy in a cell must keep pace with demand. Photoreceptors use ATP to maintain ion gradients in darkness, whereas in light they use it to support phototransduction. Matching production with consumption can be accomplished by coupling production directly to consumption. Alternatively, production can be set by a signal that anticipates...
Production of energy in a cell must keep pace with demand. Photoreceptors use ATP to maintain ion gradients in darkness, whereas
in light they use it to support phototransduction. Matching production with consumption can be accomplished by coupling production
directly to consumption. Alternatively, production can be set by a signal that anticipates...
The ATPase Inhibitory Factor 1 (IF1) is an inhibitor of the mitochondrial H+-ATP synthase that regulates the activity of both oxidative phosphorylation (OXPHOS) and cell death. Here, we have developed transgenic Tet-On and Tet-Off mice that express a mutant active form of hIF1 in the hepatocytes to restrain OXPHOS in the liver to investigate the re...
The malate-aspartate NADH shuttle (MAS) operates in neurons and other cells to translocate reducing equivalents from the cytosol to the mitochondrial matrix, thus allowing a continued flux through the glycolytic pathway and metabolism of extracellular lactate. Recent discoveries have taught us that MAS is regulated by fluctuations in cytosolic Ca(2...
Calcium signalling is fundamental to the function of the nervous system, in association with changes in ionic gradients across the membrane. While restoring ionic gradients is energetically costly, a rise in intracellular Ca(2+) acts through multiple pathways to increase ATP synthesis, matching energy supply to demand. Increasing cytosolic Ca(2+) s...
Glutamate excitotoxicity is caused by sustained activation of neuronal NMDA receptors causing a large Ca(2+) and Na(+) influx, activation of poly(ADP ribose) polymerase-1 (PARP-1), and delayed Ca(2+) deregulation. Mitochondria undergo early changes in membrane potential during excitotoxicity, but their precise role in these events is still controve...
Disruption of the Krebs cycle is a hallmark of cancer. IDH1 and IDH2 mutations are found in many neoplasms, and germline alterations in SDH genes and FH predispose to pheochromocytoma/paraganglioma and other cancers. We describe a paraganglioma family carrying a germline mutation in MDH2, which encodes a Krebs cycle enzyme. Whole-exome sequencing w...
Significance
Aerobic glycolysis is a metabolic adaptation that helps cells in a tumor meet high anabolic demands. The M2 isoform of pyruvate kinase (PKM2) is associated with aerobic glycolysis in cancer cells. Aerobic glycolysis also accounts for most of the Glc metabolized in retinas. We find that photoreceptors (PRs) in retinas, like cancer cells...
Calcium is thought to regulate respiration but it is unclear whether this is dependent on the increase in ATP demand caused by any Ca2 + signal or to Ca2 + itself. [Na+]i, [Ca2 +]i and [ATP]i dynamics in intact neurons exposed to different workloads in the absence and presence of Ca2 + clearly showed that Ca2 +-stimulation of coupled respiration is...
Transport of pyruvate into mitochondria by the mitochondrial pyruvate carrier is crucial for complete oxidation of glucose and for biosynthesis of amino acids and lipids. Zaprinast is a well-known phosphodiesterase inhibitor and lead compound for Sildenafil. We found Zaprinast alters the metabolomic profile of mitochondrial intermediates and amino...
Significance
This report shows that the reducing power in the environment influences oxidation of glutamate in a neuronal tissue. Glutamate is a neurotransmitter, and it is especially important as a metabolite because it is required for synthesis of glutathione, other amino acids, and proteins. Glutamate also is a key intermediate in glutamine-depe...
Neuronal respiration is controlled by ATP demand and Ca(2+) but the roles played by each are unknown, as any Ca(2+) signal also impacts on ATP demand. Ca(2+) can control mitochondrial function through Ca(2+)-regulated mitochondrial carriers, the aspartate-glutamate and ATP-Mg/Pi carriers, ARALAR/AGC1 and SCaMC-3, respectively, or in the matrix afte...
GDAP1 is an outer mitochondrial membrane protein that acts as a regulator of mitochondrial dynamics. Mutations of the GDAP1 gene cause Charcot-Marie-Tooth neuropathy (CMT). We show that GDAP1 interacts with the vesicle-organelle trafficking proteins RAB6B and caytaxin, which suggests that GDAP1 may participate in the mitochondrial movement within t...
It has been known for a long time that mitochondria isolated from hepatocytes treated with glucagon or Ca2+-mobilizing agents such as phenylephrine show an increase in their adenine nucleotide (AdN) content, respiratory activity,
and calcium retention capacity (CRC). Here, we have studied the role of SCaMC-3/slc25a23, the mitochondrial ATP-Mg/Pi ca...
The mitochondrial transporter of aspartate-glutamate Aralar/AGC1 is a regulatory component of the malate-aspartate shuttle. Aralar-deficiency in mouse and human causes a shutdown of brain shuttle activity and global cerebral hypomyelination. A lack of neurofilament-labelled processes is detected in the cerebral cortex, but whether different types o...
Mitochondrial carriers (MC) form a highly conserved family involved in solute transport across the inner mitochondrial membrane in eukaryotes. In mammals, ATP-Mg/Pi carriers, SCaMCs, form the most complex subgroup with four paralogs, SCaMC-1, -2, -3 and -3L, and several splicing variants. Here, we report the tissue distribution and subcellular loca...
Expression of SCaMC-1L throughout the spermatogenic stages.
The germ cells present at each stage (I–XII) of the mouse spermatogenic
cycle from intermediate spermatogonia (In) to mature sperm are pictured (adapted
from [37]).
Each stage of the spermatogenic cycle comprises a set of developing germ cells.
In the diagram, the developmental progression...
SCaMC-1 and SCaMC-1L non-annotated protein sequences used in this
study. (alphabetical order of species).
(DOCX)
COS-7 cells were grown on glass plates and transiently transfected
with SCaMC-1L-EGFP construct. The SCaMC-1L-EGFP expressing vector was
obtained subcloning the full coding sequence (amino acids1–473) of mouse
SCaMC-1L-1L into pEGFP-N. Images were taken every 15 min for 7 h using an
Axiovert 200 (Zeiss) system at 37 C with a ×40 objective using a C...
Ka/Ks ratios among mammalian SCaMC-1
and SCaMC-1L orthologues. To calculate Ka/Ks
values for SCaMC-1 and SCaMC-1L genes we
retrieved coding sequences corresponding to exons 2 to 7 of representative
mammalian and performed pairwise sequence comparisons. The results are based
on Ka/Ks values for sequences from seven representative mammals; Bos
Taurus...
Accession numbers of annotated SCaMC-1 and SCaMC-1L proteins.
(alphabetical order of species).
(DOCX)
Perinuclear honeycomb-like SCaMC-1L aggregates. A representative
image of SCaMC-1L-transfected COS-7 cells containing SCaMC-1L honeycomb-like
aggregates is shown. SCaMC-1L was detected with specific anti-SCaMC-1L antibody
visualized with a FITC-conjugated secondary antibody, mitochondrial structures
are stained with anti-COX-I antibody visualized w...
Alignment of SCaMC-1 and SCaMC-1L sequences encoded by exons 2 to
7 was performed with ClustalW program and coloured using BOXSHADE program.
(www.ch.embnet.org).
(TIF)
The C-terminal does not affect the intracellular patterns of ScaMC-1L.
(A) Representative images of SCaMC-1L-expressing COS-7 cells
showing the different intracellular patterns observed; cytosolic (a), mitochondrial
(b) and extra-mitochondrial aggregates (c). COS-7 cells were transfected with
a full-length SCaMC-1L construct unchanged at C-end, co-...
Cytosolic SCaMC-1L granules do not co-localize with late endosomal/lysosomal
markers. COS-7 cells were transiently transfected with FLAG-tagged
SCaMC-1L and 24–30 hours later co-localization was analyzed by co-staining
with specific markers. COS-7 cells were co-stained with anti-SCaMC-1L antibody
(A, B) and specific markers for late endosomes (A) a...
The aralar/AGC1 knockout (KO) mouse shows a drastic decrease in brain aspartate and N-acetylaspartate levels and global hypomyelination, which are attributed to the lack of neuron-produced NAA used by oligodendrocytes as precursor of myelin lipid synthesis. In addition, these mice have a gradual drop in brain glutamine synthesis. We show here that...
Ca(2+)-mediated mitochondrial permeability transition (mPT) is the final common pathway of stress-induced cell death in many major pathologies, but its regulation in intact cells is poorly understood. Here we report that the mitochondrial carrier SCaMC-1/SLC25A24 mediates ATP-Mg(2-)/Pi(2-) and/or HADP(2-)/Pi(2-) uptake into the mitochondria after a...
The deficiency in the mitochondrial aspartate/glutamate transporter Aralar/AGC1 results in a loss of the malate-aspartate NADH shuttle in the brain neurons, hypomyelination, and additional defects in the brain metabolism. We studied the development of cortico/hippocampal local field potential (LFP) in Aralar/AGC1 knockout (KO) mice. Laminar profile...
The calcium-binding mitochondrial carriers of glutamate/aspartate (AGCs) and ATP-Mg/Pi (SCaMCs) provide a mechanism to transmit Ca2+ signals to mitochondria independent of the entry of calcium to the organelle. The AGCs Aralar/AGC1 and citrin/ AGC2 are components of the malate aspartate NADH shuttle and citrin is also a component of the urea cycle....
In eukaryotes, cellular energy in the form of ATP is produced in the cytosol via glycolysis or in the mitochondria via oxidative phosphorylation and, in photosynthetic organisms, in the chloroplast via photophosphorylation. Transport of adenine nucleotides among cell compartments is essential and is performed mainly by members of the mitochondrial...
Tesis doctoral inédita. Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 21-12-2009 Bibliogr.: p.117-133
The glutamate-glutamine cycle faces a drain of glutamate by oxidation, which is balanced by the anaplerotic synthesis of glutamate and glutamine in astrocytes. De novo synthesis of glutamate by astrocytes requires an amino group whose origin is unknown. The deficiency in Aralar/AGC1, the main mitochondrial carrier for aspartate-glutamate expressed...
The mitochondrial aspartate-glutamate carriers (AGC) aralar (SLC25A12) and citrin (SLC25A13) are components of the malate aspartate shuttle (MAS), a major intracellular pathway to transfer reducing equivalents from NADH to the mitochondrial matrix. Aralar is the main AGC isoform present in the adult brain, and it is expressed mainly in neurons. To...