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Redox Shuttles in the Brain

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Neural Metabolism In Vivo

Part of the book series: Advances in Neurobiology ((NEUROBIOL,volume 4))

Abstract

Herein, we summarize the most relevant systems operating in brain for the transfer of reducing equivalents from NAD+/NADH or NADP+/NADPH across the inner mitochondrial membrane. The kinetic properties, the transport characteristics and the calcium activation patterns of the carriers and enzymes involved in shuttling process are described. The involvement of redox shuttles in the physiology and the pathological states of the nervous system are also discussed. The malate-aspartate shuttle (MAS) is considered to be the major redox shuttle system transferring reducing equivalents from cytosolic NAD+/NADH to mitochondria that functions in brain, mainly important in neuronal cells. The function of MAS in brain is essential for maintaining a NAD+/NADH ratio favourable for the oxidative metabolism of glucose. MAS deficiency in mice has been shown to produce severe neurological deficits and growth retardation. These mice exhibit pronounced motor coordination defects along with an impairment in myelination in the central nervous system. The existence of Aralar/AGC1 (aralar; aspartate-glutamate carrier)-knockout mice (lacking MAS activity in brain) has revealed new functions for MAS. Particularly, aralar was found to be essential in the supply of brain aspartate and N-acetylaspartate for myelin lipid synthesis and in the transmission of small Ca2+ signals to neuronal mitochondria. Interestingly, the first human patient with aralar deficiency associated to a severe hypomyelination has been recently reported. The activity of the other major redox shuttle (glycerol-3-phosphate shuttle, GPS) in brain has been long questioned. Although indirect metabolic evidence might suggest that GPS is functional in the brain; for a long time the two enzymatic constituents of GPS (cytosolic and mitochondrial glycerol 3-phosphate dehydrogenases, cGPDH and mGPDH) were not found to colocalize in the same cell type, a fact that would be required for the GPS to be functional. Besides this, no neurological disturbances have been reported in GPS-deficient mice. Up to now, cGPDH had been exclusively found in oligodendrocytes, where it could provide glycerol phosphate for phospholipid synthesis and mGPDH had been found in neurons and astrocytes, where glycerol phosphate could be used as respiratory substrate. However, recent transcriptome studies in brain have revealed the coexistence of cGPDH and mGPDH in neurons and astrocytes, supporting the possible function of GPS in these cell types. Other alternative NADH shuttles are described, particularly the citrate shuttles, malate-oxaloacetate and lactate shuttles. The citrate shuttles provide acetyl-CoA for lipid synthesis, and the citrate-pyruvate cycle, which is supposed to operate in glial cells provides also NADPH in the cytosol. These shuttles may be required when MAS is impaired; and/or in glial cells, where MAS has lower activity than in neurons. Finally, two redox systems thought to transfer reducing equivalents from mitochondria to cytosolic NADP+/NADPH are described. These shuttles may be important for biosynthetic reactions in the cytosol and may play a critical role in the cellular defense against oxidative stress. However, the existence of these alternative shuttles has not been demonstrated by reconstitution assays, and because of this, should be regarded with caution.

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Abbreviations

AAT:

aspartate aminotransferase

Ac-CoA:

acetyl-coenzyme A

ACS:

acetyl CoA synthetase-1

ACL:

ATP-Citrate lyase

AGC:

aspartate-glutamate carrier

Asp:

aspartate

AOAA:

aminooxyacetic acid

ASPA:

aspartoacylase

Asp-NAT:

L-aspartate N-acetyltransferase

CaMCs:

calcium binding mitochondrial carriers

CaU:

calcium uniporter

CIC:

tricarboxylate carrier

CS:

citrate synthetase

DHAP:

dihydroxyacetone phosphate

DIC:

dicarboxylate carrier

GABA:

α-aminobutyric acid

GAPDH:

glyceraldehyde 3-phosphate dehydrogenase

Glt:

glutamate

G3P:

glycerol 3-phosphate

G6PDH:

glucose 6-phosphate dehydrogenase

Gln:

glutamine

GPx:

glutathione peroxidase

GR:

glutathione reductase

cGPDH:

cytosolic glycerol 3-phosphate dehydrogenase

mGPDH:

mitochondrial glycerol 3-phosphate dehydrogenase

GPS:

glycerol 3-P shuttle

c/m ICDH:

cytosolic/mitochondrial NADP+-dependent isocitrate dehydrogenase

IDH:

NAD+-dependent isocitrate dehydrogenase

α-KG:

α-ketoglutarate

LDH:

lactate dehydrogenase

Mal:

malate

MAS:

malate-aspartate shuttle

MC:

mitochondrial carrier

MCT:

monocarboxylate carrier

MDH:

malate dehydrogenase

c/m ME:

cytosolic/mitochondrial malic enzyme

NAA:

N-acetyl aspartate

3-NPA:

3-nitropropionic acid

OAA:

oxalacetate

OGC:

α-ketoglutarate/malate carrier

Oxodic:

oxodicarboxylate carrier

PC:

pyruvate carboxylase

Pyr:

pyruvate

ROS:

radical oxygen species

SNP:

single nucleotide polymorphism

TCA:

tricarboxilic acid cycle

TIM:

inner membrane translocase

TOM:

outer membrane translocase

VOCC:

voltage operated calcium channel.

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Acknowledgments

We are indebted to Prof. J. Satrústegui for critical reading of the manuscript, for helpful suggestions and discussions and for support. The authors would like to thank funding from the Ministerio de Educación y Ciencia (contract grant BFU2005-C02-01, GEN2003-20235-C05-03/NAC to JS), Instituto de Salud Carlos III del Ministerio de Sanidad (PI042457 to JS), European Union (contract grant number: LSHM-CT-2006-518153 to JS); Mutua Madrileña (to BP), and the institucional support of the Ramón Areces Foundation to the Centro de Biología Molecular Severo Ochoa. The CIBER de Enfermedades Raras is an initiative of the ISCIII.

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  1. Departamento de Biología Molecular, Centro de Biología Molecular “Severo Ochoa” UAM-CSIC, Universidad Autónoma, Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), ISCIII, Cantoblanco, Madrid, Spain

    Beatriz Pardo Ph.D. & Laura Contreras

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  1. Beatriz Pardo Ph.D.
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  2. Laura Contreras
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Correspondence to Beatriz Pardo Ph.D. .

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  1. School of Medicine, Hoglund Brain Imaging Center, University of Kansas, Rainbow Blvd. 3901, Kansas City, 66160, Kansas, USA

    In-Young Choi

  2. Inst. Physique de la Matière Complexe, Labo. d'Imagerie Fonctionnelle et, Ecole Polytechnique Fédérale de Lausanne, Lausanne, 1015, Switzerland

    Rolf Gruetter

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Pardo, B., Contreras, L. (2012). Redox Shuttles in the Brain. In: Choi, IY., Gruetter, R. (eds) Neural Metabolism In Vivo. Advances in Neurobiology, vol 4. Springer, Boston, MA. https://doi.org/10.1007/978-1-4614-1788-0_29

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