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Lookup NU author(s): Professor Robert Taylor
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2020 The Authors. Published under the terms of the CC BY 4.0 licensePathogenic variants in FBXL4 cause a severe encephalopathic syndrome associated with mtDNA depletion and deficient oxidative phosphorylation. 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. 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. One-year-old Fbxl4 knockouts show a global reduction in a variety of mitochondrial proteins and mtDNA depletion, whereas lysosomal proteins are upregulated. 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. Inhibition of lysosomal function in these cells reverses the mitochondrial phenotype, whereas proteasomal inhibition has no effect. 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.
Author(s): Alsina D, Lytovchenko O, Schab A, Atanassov I, Schober FA, Jiang M, Koolmeister C, Wedell A, Taylor RW, Wredenberg A, Larsson N-G
Publication type: Article
Publication status: Published
Journal: EMBO Molecular Medicine
Year: 2020
Online publication date: 11/06/2020
Acceptance date: 02/04/2016
Date deposited: 26/06/2020
ISSN (print): 1757-4676
ISSN (electronic): 1757-4684
Publisher: Blackwell Publishing Ltd
URL: https://doi.org/10.15252/emmm.201911659
DOI: 10.15252/emmm.201911659
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