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Study sheds light on a mitochondrial disease

Study sheds light on a mitochondrial disease
CRISPR screen targeting E3 ligases identifies major regulators of Parkin-independent mitophagy A. Schematic depicting the CRISPR screening strategy. RPE1-Cas9i-mt-mKeima cells were transduced with a lentiviral CRISPR sgRNA library targeting 606 E3 ligases. sgRNA-expressing cells were selected for 7 days with puromycin (Puro) and Cas9 expression induced with doxycycline (Dox) for 9 days. Fourteen days post-transduction, half the cells were treated with antimycin and oligomycin (AO; 1 and 10 μM respectively) for 24 h, then sorted alongside untreated cells (basal mitophagy) by FACS into “high” and “low mitophagy” populations based on mt-mKeima fluorescence. Genomic DNA was extracted from sorted and unsorted reference cells, sgRNAs amplified by barcoded PCRs and samples analyzed by next-generation sequencing (NGS). B, C. Volcano plot showing the average log2 fold change and −Log10 P-value of genes in low mitophagy versus unsorted cells in the AO-induced and basal mitophagy screen for two independent biological replicates. Statistical thresholds of 2 and 3 standard deviations from the mean are indicated by dashed lines and color coding. Indicated are high-confidence (unbroken line) and lower-confidence (dashed line) candidates shown in (D–F). D, E. High-confidence candidate list of positive (decreased) and negative (enhanced) regulators of Parkin-independent-induced mitophagy. Heatmap showing the Log2 fold change of genes in low/high mitophagy versus unsorted cells in the induced and basal mitophagy screen for each of two independent biological replicates. Genes with P-values < 0.05 are indicated by an asterisk. F. Venn diagram showing the overlap of genes listed in (D) and (E) that were identified in the basal and AO-induced mitophagy screens as positive (green) and negative (magenta) regulators. Bold type indicates high-confidence hits and regular type indicates lower-confidence hits. Credit: The EMBO Journal (2023). DOI: 10.15252/embj.2022112799

Scientists at the University of Liverpool have figured out how mutations in a gene called FBXL4 can lead to an excess of mitophagy—the disposal of mitochondria, the 'power stations' within nearly all human cells.

Defects in mitophagy have been linked to neurodegenerative ailments such as Parkinson's and Alzheimer's disease and many other pathophysiological conditions. However, too much mitophagy can be detrimental as well. In this study, a team of scientists led by Professor Sylvie Urbé and Professor Michael Clague and supported by Parkinson's UK, reveal how mutations in the FBXL4 gene lead to an excess of mitophagy.

The findings show that FBXL4 controls the levels of another protein called NIX, which can dive into the mitochondria and effectively act as a notice of condemnation.

Professor Sylvie Urbé said, "From time to time, mitochondria are decommissioned and new ones are made. The old or damaged mitochondria are delivered to the cell 'breakers yard' or lysosome in a process called mitophagy. Mitophagy is important in developmental pathways but also in suppressing neurodegeneration and other pathophysiological conditions."

"Sometimes mitophagy can be over-active and patients are left with too few mitochondria for the bodies energy needs and suffer from mitochondrial depletion syndrome. This is the case for with a mutation in a gene called FBXL4."

The work is published in The EMBO Journal alongside complementary findings from laboratories in China and Australia. The findings will help to open up new avenues for treating these mitophagy related diseases.

More information: Hannah Elcocks et al, FBXL4 ubiquitin ligase deficiency promotes mitophagy by elevating NIX levels, The EMBO Journal (2023). DOI: 10.15252/embj.2022112799

Journal information: EMBO Journal
Citation: Study sheds light on a mitochondrial disease (2023, May 4) retrieved 24 July 2024 from https://medicalxpress.com/news/2023-05-mitochondrial-disease.html
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