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

OBJECTIVES: SAMM50 rs3761472 is associated with metabolic dysfunction-associated steatotic liver disease (MASLD), but its functional consequences in vivo remain unclear. We investigated whether this variant disrupts mitochondrial function and promotes MASLD progression. METHODS: Associations of rs3761472 with MASLD and liver-related traits were evaluated using Korea Biobank Array data. We generated Samm50 knock-in (KI) mice carrying the D110G substitution corresponding to human rs3761472 using CRISPR/Cas9 and assessed hepatic mitochondrial homeostasis and MASLD-related phenotypes in mice fed a normal diet or a high-fat diet. RESULTS: In human genetic analyses, rs3761472 was significantly associated with MASLD and higher serum levels of liver injury markers. Samm50-KI mice showed reduced hepatic SAMM50 expression, disrupted mitochondrial organization, impaired mitochondrial respiration and ATP production, increased mitochondrial oxidative stress, inflammatory activation, apoptosis, and liver injury. Following high-fat diet feeding, Samm50-KI mice exhibited greater hepatic lipid accumulation and liver injury, together with more pronounced insulin resistance and glucose intolerance, than wild-type mice. CONCLUSIONS: Our findings establish rs3761472 as a functional genetic variant linking mitochondrial architecture to metabolic liver disease pathogenesis, with potential relevance as a genetic biomarker for MASLD susceptibility.