Redox Shuttles in the Brain

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.