FBXL4 deficiency increases mitochondrial removal by autophagy.

David Alsina,Florian A Schober,Nils‐Göran Larsson,Camilla Koolmeister,Aleksandra Schab,Oleksandr Lytovchenko,Anna Wredenberg,Anna Wedell,Ilian Atanassov,Min Jiang,Robert W Taylor

doi:10.15252/emmm.201911659

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.

Highlights

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)
The pathophysiology of human FBXL4 deficiency causing an encephalopathic syndrome associated with mtDNA depletion has remained enigmatic
This assumption was supported by 35S labeling experiments, which showed that mitochondrial protein stability in FBXL4 knockout cells was reduced but could be rescued by inhibiting lysosomal hydrolases with ammonium chloride

Summary

Introduction

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). In order to keep the mitochondrial population of the cell in shape, several quality control mechanisms act on mitochondria. These mechanisms include the cytosolic ubiquitin–proteasome system, several intramitochondrial proteolytic systems, autophagic clearance of damaged mitochondria, and the mitochondria-derived vesicle pathway (Bragoszewski et al, 2017; Zimmermann & Reichert, 2017; Pickles et al, 2018). Mutations in Parkin and PINK1 cause early-onset forms of Parkinson’s disease, and the corresponding proteins have been reported to be involved in mitochondrial protein control (Hauser & Hastings, 2013; Moon & Paek, 2015; Hernandez et al, 2016), but their in vivo roles remain controversial (Lee et al, 2018; Sliter et al, 2018). Ubiquitination has been reported to occur in the inner mitochondrial membrane and this process may possibly contribute to fine-tune metabolism according to the energetic demand of the cell (Lavie et al, 2018)

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