Nicotinamide Riboside Corrects Metabolic Imbalances and Mitochondrial Dysfunction in Citrin Deficiency: Preclinical Findings

Synopsis

Citrin deficiency (CD) is a genetic metabolic disorder caused by loss of the mitochondrial transporter CITRIN, which plays a role in the urea cycle and malate–aspartate shuttle. Patients with CD develop fatty liver and high ammonia levels but lack effective treatments. To study this, researchers created CITRIN knockout liver cells (HepG2) using CRISPR-Cas9 technology. These cells showed increased ammonia accumulation, disrupted balance of NAD+ in the cytoplasm, and impaired glycolysis (sugar metabolism). They also had abnormal fatty acid metabolism and mitochondrial dysfunction, along with elevated cholesterol and bile acid metabolism—similar to patients with CD. Treatment with nicotinamide riboside (NR) normalized the NADH:NAD+ ratio, improving glycolysis and fatty acid oxidation, though it did not affect ammonia levels. This suggests NR can correct some metabolic problems caused by CITRIN loss, offering a potential therapeutic approach for CD and related mitochondrial disorders.

Journal

Human Molecular Genetics