Nutrient State, Aging, and Diet Modulate SAM50-Dependent Mitochondrial Remodeling and Systemic Metabolic Signatures

Although Sorting and Assembly Machinery 50 (SAM50) is known to regulate nutritional and metabolic stress related to ageing, its exact role is not well understood. This experimental study combines both human and animal models to understand the role that SAM50 plays in nutrient, age-related metabolic remodeling. We also wanted to define the clinical relevance of SAMM50 genetic variation in human disease. Our study integrated clinical and genetic data from three large and independent human biobanks to assess the clinical implications of genetic variation in SAMM50. We then conducted mechanistic studies in mice using Serial Block-Face Scanning Electron Microscopy and Transmission Electron Microscopy for three-dimension analysis of mitochondrial morphology, immunoblotting, metabolomics/lipidomics, and assessment of metabolic parameters in models of fasting, aging, and a high-fat diet (HFD). Descriptive and inferential statistics were used to describe and test associations in GraphPad prism version 10. Our study demonstrated that common genetic variation within the SAMM50 genetic locus was significantly associated with liver-related metabolic disorders. In mice, nutrient status was associated with expression levels of Sam50 and proteins involved in the respiratory complex. Aging was associated with impaired mitochondria, decreased Sam50 expression, and increased triglyceride and lipid peroxidation, with increased lipid droplet-mitochondria contacts. An HFD was associated with a reduction in Sam50 expression, disruption of mitochondrial structure, and metabolic dysfunction, effects that were only partly reversed by returning to a normal diet. Our results demonstrate that SAM50 expression is associated with nutrient state and age-related signals, thereby orchestrating mitochondrial structure to influence systemic metabolic health.