The Roles of F-box and Leucine-Rich Repeat Protein 4 (FBXL4) in Mitochondrial Encephalopathy and T-cell Acute Lymphoblastic Leukemia

The F-box and leucine-rich repeat factor (FBXL4) locus is altered in two distinct diseases, a pediatric mitochondrial encephalopathy associated with early death, and the highly aggressive hematological malignancy T-cell Acute Lymphoblastic Leukemia (T-ALL). As an F-box protein, FBXL4 is predicted to target specific protein substrates for proteasomal degradation. Notably, not much is known about the roles of FBXL4 in homeostasis or disease, and thus I generated conditional Fbxl4 knockout mice to characterize the contributions of Fbxl4 to mitochondrial encephalopathy and to T-ALL. Homozygous mutations in FBXL4 are associated with pediatric-onset mitochondrial encephalopathy, but the molecular and cellular mechanisms driving disease pathogenesis are unknown. Here, I show that constitutive loss of Fbxl4 recapitulates key features of human mitochondrial encephalopathy, including microcephaly, failure to thrive, and perinatal lethality. Moreover, Fbxl4 inactivation drives profound metabolic alterations in the perinatal period. On the cellular level, loss of Fbxl4 results in mitochondria DNA depletion and disrupts oxidative phosphorylation and mitochondria membrane potential. Isolation of the FBXL4 protein complex reveals that FBXL4 interacts with a diverse set of mitochondrial factors crucial for normal mitochondrial function. Overall, these findings underscore the importance of FBXL4 in development, metabolism, and mitochondrial dynamics, and may be used to develop novel therapies for patients with mitochondrial encephalopathy associated with FBXL4 mutations and for patients with 6q- T-ALL.