Encephalopathy is a term for any disease that alters the function of the brain. Encephalopathy due to defective mitochondrial and peroxisomal fission (EMPF1) is a rare neurodevelopmental disease that currently has no effective treatment. Dynamin-related protein 1 (DRP1) is a large GTPase that mediates fission of mitochondria and peroxisomes. Patients with mutations in the gene encoding DRP1 (dynamin 1 like, DNM1L) develop EMPF1, which is characterized by refractory seizures and eventual neurologic decline. In this study (Robertson et al., 2023), Vivian Gama and colleagues use patient-derived fibroblasts to help decipher the aetiology of EMPF1. In addition to the characteristic elongated mitochondrial morphology due to lack of fission, the authors show, using super-resolution and electron microscopy, that these hyperfused mitochondria have aberrant cristae structures. These aberrations are associated with hyperpolarized mitochondrial membrane potential, increased proton leakage, upregulation of glycolysis and a lower coupling efficiency of the electron transport chain. Fibroblasts from EMPF1 patients also exhibit elongated peroxisomes with perturbed metabolic activity, including impairment of the methionine cycle and synthesis of pyrimidine nucleotides. Together, these data help elucidate the mechanistic underpinnings of EMPF1, showing that altered mitochondrial and peroxisomal fission have a significant impact on the metabolic capabilities of DRP1 mutant cells.