Regulatory Role of Mitochondrial Protein FAM210A in Liver Homeostasis and Repair

Metabolic-associated fatty liver disease (MAFLD) is a leading cause of liver cirrhosis and hepatocellular carcinoma worldwide. Mitochondrial dynamics play a critical role in maintaining liver health and homeostasis; however, the underlying mechanisms in MAFLD and liver repair remain unclear. In this study, we identified Family with sequence similarity 210, member A (FAM210A) as a novel hepatocyte-enriched protein with distinct roles in MAFLD pathogenesis during juvenile development and liver repair in adulthood. Hepatocyte-specific Fam210a knockout ( Fam210a HKO ) mice exhibited growth restriction at 3 to 5 weeks old, characterized by reduced body and liver weight. The Fam210a HKO liver displayed abnormal fat accumulation, decreased glycogen storage, and impaired mitochondrial activity, profoundly affecting lipid metabolism. Systemically, Fam210a loss led to reduced serum glucose levels in the fasting-refeeding state, though glucose tolerance and insulin sensitivity remained unchanged. Strikingly, these metabolic abnormalities resolved in adult Fam210a HKO mice, which exhibited normal body and liver weight, glucose levels, fat accumulation, and mitochondrial protein expression, except for persistently reduced glycogen storage. Transcriptomic analysis revealed significant downregulation of fatty acid metabolism, amino acid catabolism, and small molecule catabolic pathways, while nuclear division, chromosome segregation, cell cycle, and organelle fission pathways were markedly upregulated in the Fam210a HKO liver at 5 weeks of age. These findings suggest active hepatocyte proliferation and liver regeneration occurring after the MAFLD-like phenotype in Fam210a HKO liver. This was further supported by electron microscopy and Ki67 immunostaining, confirming increased hepatocyte proliferation in Fam210a HKO livers at this stage. Mitochondrial proteomics analysis reveals that pathways related to nucleoplasm are enriched in in Fam210a HKO mitochondria, while pathways related to membrane, peroxisome and protein-containing complex are downregulated. Mechanistically, we found that FAM210A deficiency disrupted mitochondrial remodeling by promoting excessive OPA1 cleavage through its interaction with the mitochondrial protease YME1L, which leads to the metabolic dysfunction of Fam210a -deficiency liver in early life. Overall, our findings establish FAM210A as a key regulator of liver mitochondrial dynamics and provide new insights into its role in MAFLD pathogenesis and liver repair. This study was supported by NIH-R01DK136722 (F.Y.) and Older Americans Independence Center (OAIC) Pepper Junior Scholar Award (F.Y.) with parent grant NIH-P30AG028740. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.