Mitofusin 2 (MFN2) coordinates mitochondrial dynamics through its roles in mitochondrial fission, tethering and PINK1-parkin-mediated mitophagy. In addition to parkin, evidence suggests other E3 ubiquitin ligases regulate MFN2 in specific subcellular compartments. Recently, Srinivasa Srinivasula and colleagues found that the endosomal E3 ligase RFFL colocalises with damaged mitochondria and influences parkin recruitment. In this study (Narendradev et al., 2025), the same group verifies that RFFL directly interacts with and ubiquitylates MFN2, targeting it for proteasomal degradation. Furthermore, RFFL-knockout cells demonstrate hyperfused mitochondrial networks similar to those observed in Charcot–Marie–Tooth disease type 2A (CMT2A), which is caused by variants in MFN2, suggesting that RFFL-mediated regulation of MFN2 is important for mitochondrial network homeostasis. Importantly, the authors show that CMT2A mutant MFN2 proteins are more sensitive to RFFL-mediated degradation and that co-expression of exogenous RFFL with MFN2 mutants rescues hyperfused mitochondria, highlighting a possible new strategy for treating CMT2A. Finally, RFFL localises to mitochondria–endosome contact sites, which are known to facilitate lipid exchange between these organelles. Overexpression of RFFL significantly increases the size and number of lipid droplets, a feature previously associated with MFN2 knockdown, revealing a potential new role for MFN2 in crosstalk between endosomes, mitochondria and lipid droplets for further exploration.
