Back to the IRBLleida Fridays: BXL4 deficiency increases mitochondrial removal by autophagy

Friday seminar
divendres, 24 juliol 20

David Alsina

About me:

I studied a Biotechnology degree at Universitat de Lleida followed by a Master's degree in Biotechnology in Health Sciences. I did my PhD under the supervision of Dr Jordi Tamarit and Dr Joaquim Ros studying frataxin function and its relation to iron metabolism and oxidative stress using yeast models.

After completing my PhD, I wanted to expand my knowledge in mitochondrial biology and in 2017 I joined Professor Nils-Göran Larsson's group at Karolinska Institutet in Stockholm as a postdoctoral researcher. The lab uses mouse and cellular models to study several aspects of mitochondrial biology such as (1) mitochondrial DNA organization, maintenance and expression; (2) the impact of mitochondrial dysfunction in diseases like neurodegeneration and cancer; (3) and the study of mitochondrial diseases. During my time as a postdoc I have been involved in studying the function of Fbxl4, a gene with described pathogenic variants that lead to a mitochondrial DNA depletion syndrome (MTDPS13). Despite being a rare disease, it is one of the most common mutated genes in children presenting lactic acidosis.

A part from this project, I am working in other projects aimed to identify new genes involved in mtDNA replication regulation and in the generation of new mouse models of mitochondrial diseases.


Hora: 15.30

Lloc: online


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 FBXL 4 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, these results show that FBXL4 prevents mitochondrial removal via autophagy and that loss of FBXL4 leads to decreased mitochondrial content and mitochondrial disease.