FBXL4 Deficiency leads to increased clearance of Mitochondria

Mitochondria-Speaker Nils-Göran LarssonThe Organizing Committee of Targeting Mitochondria 2020 Congress is honored to announce the participation of Prof. Nils-Göran Larsson from Karolinska Institutet, Sweden.
Prof. Larsson will give a talk entitled "FBXL4 Deficiency leads to increased clearance of Mitochondria"
during the congress which will be held on October 29-30, 2020.

Summary of the Talk: Pathogenic mutations inFBXL4 lead to OXPHOS defects and mtDNA depletion associated with encephalopathy, developmental regression, epileptic seizures and other types of neurological deficits. Despite the frequent occurrence and severe consequences of FBXL4 mutations in humans, the function of the FBXL4 protein has remained poorly understood. We generated mice that lack FBXL4 and show that they recapitulate important aspects of the human disease, including mtDNA depletion. Using proteomic approaches, we found a general decrease of mitochondrial proteins accompanied by an increase in lysosomal proteins inFbxl4 knockout mice as well as in fibroblasts derived from patients with loss-of-functionFBXL4mutations. Unexpectedly, expression of nuclear genes encoding mitochondrial proteins and mitochondrial translation remained unaffected in the absence of FBXL4. We present data showing that the molecular phenotype instead is explained by increased autophagic removal of mitochondria, leading to a global decrease of cellular mitochondrial content. Treatment with the lysosomal inhibitor ammonium chloride rescues mitochondrial protein stability inFBXL4knockout human cells, consistent with the hypothesis that increased autophagy flux is an important pathophysiological event. Further studies are needed to explore the therapeutic potential of these findings, in particular, whether inhibition of autophagy may provide a strategy for treatment of affected patients.   

Targeting Mitochondria 2020 Congress
October 29-30, 2020

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