The SAMM50 rs3761472 causes mitochondrial dysfunction and metabolic dysfunction-associated steatotic liver disease

Genome-wide association studies (GWAS) have identified the SAMM50 rs3761472 single nucleotide polymorphism (SNP) as a risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD), although its in vivo functions remain unclear. SAMM50 encodes a mitochondrial outer membrane protein critical for maintaining mitochondrial structure. To investigate the biological effects of rs3761472, we generated Samm50-knock-in (KI) mice harboring a D110G substitution using CRISPR/Cas9. This variant impaired mitochondrial integrity by downregulating key regulators of mitochondrial architecture, dynamics, and quality control. This contributed to reduced ATP production and elevated oxidative stress, inflammation, and hepatocyte death. The mutation also induced insulin resistance and glucose intolerance. Samm50-KI mice fed a high-fat diet exhibited pronounced hepatic lipid accumulation and liver injury, highlighting its pathogenic role in MASLD progression. Our findings demonstrate that SAMM50 rs3761472 is a critical driver of mitochondrial dysfunction and MASLD susceptibility, supporting its potential as a therapeutic target and its relevance to precision medicine.