![]() Mitochondrial diseases are a heterogeneous group of inherited metabolic disorders characterized by deficient oxidative phosphorylation (OXPHOS) that leads to a variety of secondary metabolic defects and pleiotropic clinical phenotypes (Gorman et al, 2016). Interventions to stop the increased mitochondrial turnover should be considered as a potential treatment for this disease. The obtained results shed light on the pathophysiology of the disease and suggest that Fbxl4 participates in mitochondrial quality control. Although the remaining mitochondria are fully functional, their numbers are insufficient to prevent disease. We report that Fbxl4 is involved in mitochondrial quality control and that its absence causes an increased lysosomal turnover of mitochondria leading to a decreased cellular mitochondrial content. Here, we combined three different models, i.e., knockout mice, patient-derived fibroblasts, and a CRISPR/Cas9 knockout human cell line, to study the physiological role of Fbxl4. The pathophysiology of the disease and the function of Fbxl4 are poorly understood. Pathogenic variants of FBXL4 cause an encephalopathic syndrome in children accompanied by lactic acidosis and mitochondrial DNA depletion (MTDPS13). ![]() Taken together, the results we present here show that FBXL4 prevents mitochondrial removal via autophagy and that loss of FBXL4 leads to decreased mitochondrial content and mitochondrial disease. Inhibition of lysosomal function in these cells reverses the mitochondrial phenotype, whereas proteasomal inhibition has no effect. ![]() Fibroblasts from patients with FBXL4 deficiency and human FBXL4 knockout cells also have reduced steady-state levels of mitochondrial proteins that can be attributed to increased mitochondrial turnover. One-year-old Fbxl4 knockouts show a global reduction in a variety of mitochondrial proteins and mtDNA depletion, whereas lysosomal proteins are upregulated. Surprisingly, the few surviving animals are apparently normal until the age of 8–12 months when they gradually develop signs of mitochondrial dysfunction and weight loss. To gain further insight into the enigmatic pathophysiology caused by FBXL4 deficiency, we generated homozygous Fbxl4 knockout mice and found that they display a predominant perinatal lethality. Pathogenic variants in FBXL4 cause a severe encephalopathic syndrome associated with mtDNA depletion and deficient oxidative phosphorylation.
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