Catalytic activity of FAHD1 correlates with nuclear morphology and proteomic states in human osteosarcoma cells

FAHD1 is a mitochondrial enzyme involved in oxaloacetate metabolism, with emerging links to cellular redox balance, Ca²⁺-metabolism, and structural features. Building on previous work (Heberle et al. Sci Rep 14:9231, 2024), we investigated how overexpression of human FAHD1 (hFAHD1) variants, including wild-type, the catalytically inactive hFAHD1-K123A, and the hyperactive hFAHD1-T192S, affects nuclear morphology in U2OS osteosarcoma cells. Using high-content microscopy and automated classification, we observed variant-specific shifts in nuclear shape distributions. Notably, expression of K123A was associated with a higher frequency of large, rounded nuclei and a reduction in elongated forms, while the T192S variant produced subtler changes. By aligning morphological clusters with available proteomic profiles, we identified suggestive correlations with differences in biosynthetic activity and chromatin organization. These findings indicate that altered FAHD1 activity is correlated with changes in nuclear morphology and may be associated with broader cellular organization. Our results are descriptive and hypothesis-generating, highlighting possible links between mitochondrial metabolic states and nuclear architecture that warrant further validation.