Odd-chain dicarboxylic acid feeding recapitulates the biochemical phenotype of glutaric aciduria type 1 in mice

ABSTRACT Glutaric aciduria type-1 (GA1) is an inherited mitochondrial neurometabolic disorder with a poorly understood pathogenesis and unmet medical needs. GA1 can be diagnosed via its hallmark biochemical signature consisting of glutaric aciduria, 3-hydroxyglutaric aciduria, and increased plasma glutarylcarnitine. These glutaryl-CoA-derived metabolites are thought to originate solely in the mitochondria. Here, we demonstrate that wild-type mice fed an 11-carbon odd-chain dicarboxylic acid (undecanedioic acid, DC 11 ) recreates the biochemical phenotype of GA1. Odd-chain dicarboxylic acids like DC 11 are not present in food but can arise from several endogenous processes, such as lipid peroxidation and fatty acid ω-oxidation. DC 11 is chain-shortened in peroxisomes to glutaryl (DC 5 )-CoA, which then gives rise to the GA1-like pattern of DC 5 metabolites in urine, tissues, and blood. Glutaric acid released from peroxisomes during DC 11 chain-shortening can enter mitochondria, be activated to CoA by the enzyme succinyl-CoA:glutarate-CoA transferase (SUGCT), and become substrate for glutaryl-CoA dehydrogenase (GCDH), the enzyme that is mutated in GA1. Our data provide proof-of-concept that the generation of dicarboxylic acids by ω-oxidation, which is stimulated during the same catabolic states known to trigger acute encephalopathy in GA1, may exacerbate disease by increasing the glutaryl-CoA substrate load in mitochondria.