MCD enzyme deficiency drives early mortality and multiorgan metabolic disruption in Dahl salt-sensitive rats

Malonyl-CoA decarboxylase (MCD), encoded by Mlycd, plays a critical role in regulating malonyl-CoA levels, fatty acid oxidation, and glucose metabolism. To investigate the systemic effects of Mlycd deficiency, we generated a genetically modified rat model with partial loss of Mlycd. Due to high preweaning mortality in homozygous mutants, we focused on heterozygous and wild-type animals for cross-tissue targeted proteomic and metabolomic analyses. Alterations in metabolic and stress-related pathways were observed across the heart, kidney, liver, plasma, and urine. Enrichment of oxidative phosphorylation, fatty acid metabolism, immune responses, and autophagy-related signaling was noted. Elevated levels of oxidative stress-related proteins and disrupted autophagy regulation were particularly evident in the kidney and liver. Additionally, several lysine conjugates, including trimethyllysine, N-methyl-pipecolic acid, and Nε-acetyl-lysine, were decreased in the kidney. These findings demonstrate the widespread physiological impact of Mlycd deficiency and highlight its role in coordinating energy metabolism and cellular stress responses across multiple organ systems.