Abstract
Defects in energy metabolism are potential pathogenic mechanisms in amyotrophic lateral sclerosis (ALS), a rapidly fatal disease with no cure. The mechanisms through which this occurs remain elusive and their understanding may prove therapeutically useful. We used metabolomics and stable isotope tracers to examine metabolic changes in a well-characterized cell model of familial ALS, the motor neuronal NSC-34 line stably expressing human wild-type Cu/Zn superoxide dismutase (wtSOD1) or mutant G93A (G93ASOD1). Our findings indicate that wt and G93ASOD1 expression both enhanced glucose metabolism under serum deprivation. However, in wtSOD1 cells, this phenotype increased supply of amino acids for protein and glutathione synthesis, while in G93ASOD1 cells it was associated with death, aerobic glycolysis, and a broad dysregulation of amino acid homeostasis. Aerobic glycolysis was mainly due to induction of pyruvate dehydrogenase kinase 1. Our study thus provides novel insight into the role of deranged energy metabolism as a cause of poor adaptation to stress and a promoter of neural cell damage in the presence of mutant SOD1. Furthermore, the metabolic alterations we report may help explain why mitochondrial dysfunction and impairment of the endoplasmic reticulum stress response are frequently seen in ALS.Electronic supplementary materialThe online version of this article (doi:10.1007/s12035-015-9165-7) contains supplementary material, which is available to authorized users.
Highlights
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting upper and lower motor neurons, usually leading to death in about 3–5 years after the onset of symptoms
The increased susceptibility of G93ASOD1 motor neuronal cells to serum deprivation [14, 13], as well as the caspase-inducing activity of mutant SOD1, has previously been reported. This pointed to mitochondrial involvement in the death of motor neurons, death was driven by a caspase-independent pathway [19]
The increase in the M2 isoform of pyruvate kinase may indicate a more subtle regulation of pyruvate kinase activity as this isoform responds to the availability of its substrate and to the upstream glycolytic intermediate fructose-1,6-biphosphate, the amino acid serine, To further investigate the cause of lactate accumulation, we investigated whether the entry of pyruvate into the tricarboxylic acid (TCA) cycle in the glycine 93 to alanine (G93A)-NSC was limited by the restriction of pyruvate dehydrogenase complex activity, which metabolizes pyruvate to acetyl-CoA
Summary
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting upper and lower motor neurons, usually leading to death in about 3–5 years after the onset of symptoms. 20 % of fALS and 5 % of apparent sALS patients have mutations in the Cu/Zn superoxide dismutase (SOD1) gene and the pathophysiological role of these mutations, which cause multiple changes in the different cell types of the central nervous system, are still not clear [1]. Mice, and cells expressing mutant SOD1 proteins have been studied extensively as a model of ALS. SOD1 is primarily a cytosolic protein, but is present in mitochondria, where it localizes mostly in the intermembrane space [2]. This enzyme catalyzes the dismutation of the superoxide radical, and has a function in oxidative stress protection. SOD1 has been shown to transmit signals from oxygen and glucose to regulate respiration [3]
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