Molecular metabolismJul 17, 2026

SAMM50 gene variant linked to energy problems in cells and worsening fatty liver disease related to metabolism

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Jul 18, 2026

Abstract

The SAMM50 rs3761472 variant is associated with impaired mitochondrial function and metabolic liver disease.

The rs3761472 single-nucleotide polymorphism is linked to metabolic dysfunction-associated steatotic liver disease (MASLD).
Knock-in mice with the D110G substitution show impaired mitophagy and reduced ATP production.
Elevated oxidative stress and inflammatory activation are observed in the liver of these mice.
Under high-fat diet conditions, the variant leads to hepatic steatosis, liver injury, insulin resistance, and glucose intolerance.
These findings suggest a direct role of rs3761472 in the pathogenesis of metabolic liver disease.

Simplified

Mitochondria play a key role in metabolic liver disease, yet how inherited genetic variation perturbs mitochondrial integrity in vivo remains poorly understood. Here, we demonstrate that SAMM50 rs3761472, a population-enriched single-nucleotide polymorphism (SNP) previously associated with metabolic dysfunction-associated steatotic liver disease (MASLD), exerts a direct functional impact on mitochondrial function. We performed genome-wide and phenome-wide analyses across large Biobank cohorts and identified a significant association between rs3761472 and MASLD. To define its underlying mechanism, we generated Samm50 knock-in (KI) mice carrying the rs3761472 corresponding D110G substitution using CRISPR/Cas9 genome editing. KI mice exhibited impaired mitophagy, reduced ATP production, elevated oxidative stress, and inflammatory activation in the liver, accompanied by disrupted mitochondrial organization. Under high-fat diet conditions, the variant drove hepatic steatosis, liver injury, insulin resistance, and glucose intolerance, recapitulating key features of MASLD. Together, 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.

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SAMM50 gene variant linked to energy problems in cells and worsening fatty liver disease related to metabolism

Abstract

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