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

Malonyl-CoA decarboxylase (MCD), encoded by <i>Mlycd</i>, plays a critical role in regulating malonyl-CoA levels, fatty acid oxidation, and glucose metabolism. To investigate the systemic effects of <i>Mlycd</i> deficiency, we generated a genetically modified rat model with partial loss of <i>Mlycd</i>. 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, <i>N</i>-methyl-pipecolic acid, and <i>Nε</i>-acetyl-lysine, were decreased in the kidney. These findings demonstrate the widespread physiological impact of <i>Mlycd</i> deficiency and highlight its role in coordinating energy metabolism and cellular stress responses across multiple organ systems.