FBXL4 deficiency increases mitochondrial removal by autophagy.

EMBO Molecular Medicine
David AlsinaNils-Göran Larsson

Abstract

Pathogenic 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.

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Citations

Dec 15, 2020·FEBS Letters·Roberta FilogranaNils-Göran Larsson
Oct 17, 2020·The Journal of Biological Chemistry·David L ProleNick S Jones
Nov 20, 2020·Biomolecules·Prasad SulkshaneMichael H Glickman
Jan 18, 2021·The Journal of Biological Chemistry·David L ProleNick S Jones
Mar 19, 2021·Cell & Bioscience·Qiyin ZhouYi Sun
Jul 3, 2021·International Journal of Molecular Sciences·Javier RamónRamon Martí

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Datasets Mentioned

BETA
PXD018639

Methods Mentioned

BETA
ubiquitination
PCR
electrophoresis
biopsies
confocal microscopy
GTPases
DNA assay
Protein Assay
acetylation

Software Mentioned

Mascot
R R Development Core Team
Proteome Discoverer
MitoCarta
ggplot
Andromeda
ImageJ
limma
R script
GraphPad Prism

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