Expression of mitochondrial branched-chain aminotransferase and α-keto-acid dehydrogenase in rat brain: implications for neurotransmitter metabolism

Jeffrey T Cole,Susan M Hutson,Andrew J Sweatt

doi:10.3389/fnana.2012.00018

Abstract

In the brain, metabolism of the essential branched chain amino acids (BCAAs) leucine, isoleucine, and valine, is regulated in part by protein synthesis requirements. Excess BCAAs are catabolized or excreted. The first step in BCAA catabolism is catalyzed by the branched chain aminotransferase (BCAT) isozymes, mitochondrial BCATm and cytosolic BCATc. A product of this reaction, glutamate, is the major excitatory neurotransmitter and precursor of the major inhibitory neurotransmitter γ-aminobutyric acid (GABA). The BCATs are thought to participate in a α-keto-acid nitrogen shuttle that provides nitrogen for synthesis of glutamate from α-ketoglutarate. The branched-chain α-keto acid dehydrogenase enzyme complex (BCKDC) catalyzes the second, irreversible step in BCAA metabolism, which is oxidative decarboxylation of the branched-chain α-keto acid (BCKA) products of the BCAT reaction. Maple Syrup Urine Disease (MSUD) results from genetic defects in BCKDC, which leads to accumulation of toxic levels of BCAAs and BCKAs that result in brain swelling. Immunolocalization of BCATm and BCKDC in rats revealed that BCATm is present in astrocytes in white matter and in neuropil, while BCKDC is expressed only in neurons. BCATm appears uniformly distributed in astrocyte cell bodies throughout the brain. The segregation of BCATm to astrocytes and BCKDC to neurons provides further support for the existence of a BCAA-dependent glial-neuronal nitrogen shuttle since the data show that BCKAs produced by glial BCATm must be exported to neurons. Additionally, the neuronal localization of BCKDC suggests that MSUD is a neuronal defect involving insufficient oxidation of BCKAs, with secondary effects extending beyond the neuron.

Highlights

The three nutritionally essential branched chain amino acids (BCAAs), leucine, isoleucine, and valine, contribute nitrogen to the glutamate/glutamine cycle (Hutson et al, 2005; Yudkoff et al, 2005)
The key findings of this study are the apparent restriction of BCATm expression to astrocytes, Bergmann glial cells and spinal cord radial glia, while branched-chain α-keto acid dehydrogenase enzyme complex (BCKDC)-E1α is expressed by neurons and ependymal cells
In light of the white matter edema that occurs in Maple Syrup Urine Disease (MSUD), is that BCKDC-E1α, which is defective in MSUD, is not present in white matter tracts

Summary

INTRODUCTION

The three nutritionally essential branched chain amino acids (BCAAs), leucine, isoleucine, and valine, contribute nitrogen to the glutamate/glutamine cycle (Hutson et al, 2005; Yudkoff et al, 2005). These amino acids provide approximately 30–50% of the nitrogen for de novo glutamate synthesis in astrocytes (Kanamori et al, 1998). BCAT isozymes-cytosolic (BCATc) and mitochondrial (BCATm) (Ichihara, 1985) Both BCAT enzymes reversibly transfer the α-amino group of a BCAA to an amino group acceptor, generally α-ketoglutarate. BCATc, but not BCATm expression, was diminished after a brain injury These combined changes were associated with significantly altered excitability in the hippocampus and impaired cognition. Understanding the distribution of these key enzymes will have a major impact on the understanding, and possibly treatment, of both traumatic brain injury and MSUD

MATERIALS AND METHODS

Findings

DISCUSSION