Ubiquitin-dependent control of mitochondrial dynamics is important for protein quality and neuronal integrity. Mitofusins, mitochondrial fusion factors, can integrate cellular stress through their ubiquitylation, which is carried out by multiple E3 enzymes in response to many different stimuli. However, the molecular mechanisms that enable coordinated responses are largely unknown. Here we show that yeast Ufd2, a conserved ubiquitin chain-elongating E4 enzyme, is required for mitochondrial shape adjustments. Under various stresses, Ufd2 translocates to mitochondria and triggers mitofusin ubiquitylation. This elongates ubiquitin chains on mitofusin and promotes its proteasomal degradation, leading to mitochondrial fragmentation. Ufd2 and its human homologue UBE4B also target mitofusin mutants associated with Charcot-Marie-Tooth disease, a hereditary sensory and motor neuropathy characterized by progressive loss of the peripheral nerves. This underscores the pathophysiological importance of E4-mediated ubiquitylation in neurodegeneration. In summary, we identify E4-dependent mitochondrial stress adaptation by linking various metabolic processes to mitochondrial fusion and fission dynamics. [Display omitted] • Ubiquitin enables cytosolic-mitochondrial communication via mitofusins • Ufd2 translocates to mitochondria, ubiquitylates mitofusin, and prevents fusion events • Mitofusins prove a role of Ufd2 as E4 enzyme in ubiquitin chain elongation • Ufd2/UBE4B depletion rescues turnover of CMT2A mitofusin disease mutants Anton et al. uncover the regulation of mitofusin by the E4 ligase Ufd2/UBE4B, as a response to stress and disease mutations. This highlights the role of ubiquitin signaling in integrating mitochondrial stress and thereby impacting cellular health control. [ABSTRACT FROM AUTHOR]