Odd‐Chain Dicarboxylic Acid Feeding Produces a Glutaric Aciduria Type 1–Like Metabolic Signature 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 ) recreate 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 for reactivation by the enzyme succinyl‐CoA:glutarate‐CoA transferase (SUGCT) and become substrate for glutaryl‐CoA dehydrogenase (GCDH), the enzyme that is deficient 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.