A non-canonical mitochondrial function of MAFG drives HCC progression by stabilizing PGAM5 to promote fission

Abstract Excessive mitochondrial fission is a hallmark of hepatocellular carcinoma (HCC), yet the upstream regulatory mechanisms driving this pathological process remain poorly understood. While the transcription factor V-Maf avian musculoaponeurotic fibrosarcoma oncogene homolog G (MAFG) is known to be overexpressed in HCC, its potential role in mitochondrial dynamics has not been explored. In this study, we identify a novel, non-canonical, extra-nuclear function of MAFG in promoting mitochondrial fission and HCC malignancy. Mechanistically, we demonstrate that a subpopulation of MAFG is detected in the mitochondrial fraction where it directly interacts with the protein phosphatase PGAM5. By binding to the Arg251 residue of PGAM5 via its Lys81 residuum binding suppresses PGAM5 ubiquitination. The resulting stabilization of PGAM5 enhances the dephosphorylation of dynamin-related protein 1 (DRP1) at Ser637, thereby driving excessive mitochondrial fission and fueling HCC progression. Functionally, ectopic expression of PGAM5 rescues the impaired malignant phenotypes caused by MAFG knockdown, whereas PGAM5 inhibition attenuates MAFG-driven oncogenesis. Clinical analyses further confirm that the MAFG-PGAM5-DRP1 axis is significantly activated in HCC tissues and strongly correlates with poor patient prognosis. Our findings reveal a previously unrecognized, transcription-independent oncogenic pathway in which mitochondrial MAFG stabilizes PGAM5 to orchestrate pathological fission. These results suggest that targeting the specific MAFG-PGAM5 interaction may represents a promising therapeutic strategy for the treatment of HCC.