ArticleGenes & development2020
ALS/FTD-associated protein FUS induces mitochondrial dysfunction by preferentially sequestering respiratory chain complex mRNAs.
Article in Genes & development, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.
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Who cites it
55 citing papers in PubMed.
- Compartment-specific transcriptome of motor neurons reveals impaired extracellular matrix signaling and activated cell cycle kinases in FUS-ALS.Neurobiology of disease · 2026Article
- Hypoxic stress is an early pathogenic event in human VCP-mutant ALS astrocytes.Stem cell reports · 2026Article
- Retrospective Study of the Physiological and Molecular Features of the S-FUS (1-359) Mouse Transgenic Model with an ALS-like Phenotype: Lifespan, Body Weight Dynamics, Movement Disorders, and Dysregulation of the Dopaminergic System.Journal of molecular neuroscience : MN · 2026Article
- Traditional Chinese botanical medicines and plant-derived bioactive compounds in amyotrophic lateral sclerosis: mechanistic evidence, translational challenges, and therapeutic opportunities.Frontiers in pharmacology · 2026Review
- PPA1 Facilitates Thermogenesis in Brown and Beige Fat by Regulating the Mitochondrial Localization of FUS.Current medical science · 2025Article
- Brain transcriptomics highlight abundant gene expression and splicing alterations in non-neuronal cells in aFTLD-U.Acta neuropathologica · 2025Article
- Stress granules attenuate protein nanoparticle induced osmotic imbalance via membrane potential restoration.Scientific reports · 2025Article
- Ropinirole Functions Through a Dopamine Receptor D2-Independent Mechanism to Ameliorate Amyotrophic Lateral Sclerosis Phenotypes in TARDBP-Mutant iPSC-Derived Motor Neurons.Journal of neurochemistry · 2025Article
- DNA nanoflower Oligo-PROTAC for targeted degradation of FUS to treat neurodegenerative diseases.Nature communications · 2025Article
- Targets and Gene Therapy of ALS (Part 1).International journal of molecular sciences · 2025Review
- Mitochondrial respiratory complex IV deficiency recapitulates amyotrophic lateral sclerosis.Nature neuroscience · 2025Article
- Dysfunctional Mitochondria Characterize Amyotrophic Lateral Sclerosis Patients' Cells Carrying the p.G376DAntioxidants (Basel, Switzerland) · 2025Article
- Emerging Ferroptosis Involvement in Amyotrophic Lateral Sclerosis Pathogenesis: Neuroprotective Activity of Polyphenols.Molecules (Basel, Switzerland) · 2025Review
- Targeting common disease pathomechanisms to treat amyotrophic lateral sclerosis.Nature reviews. Neurology · 2025Review
- The Underestimated Role of Iron in Frontotemporal Dementia: A Narrative Review.International journal of molecular sciences · 2024Review
- Nuclear pore dysfunction and disease: a complex opportunity.Nucleus (Austin, Tex.) · 2024Review
- Nuclear pore and nucleocytoplasmic transport impairment in oxidative stress-induced neurodegeneration: relevance to molecular mechanisms in Pathogenesis of Parkinson's and other related neurodegenerative diseases.Molecular neurodegeneration · 2024Review
- Axonopathy Underlying Amyotrophic Lateral Sclerosis: Unraveling Complex Pathways and Therapeutic Insights.Neuroscience bulletin · 2024Review
- Review
- Regulation of DNA damage response by RNA/DNA-binding proteins: Implications for neurological disorders and aging.Ageing research reviews · 2024Review
Corrections and comments
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Authors and funding
8 authors.
Funding
Abstract
Dysregulation of the DNA/RNA-binding protein FUS causes certain subtypes of ALS/FTD by largely unknown mechanisms. Recent evidence has shown that FUS toxic gain of function due either to mutations or to increased expression can disrupt critical cellular processes, including mitochondrial functions. Here, we demonstrate that in human cells overexpressing wild-type FUS or expressing mutant derivatives, the protein associates with multiple mRNAs, and these are enriched in mRNAs encoding mitochondrial respiratory chain components. Notably, this sequestration leads to reduced levels of the encoded proteins, which is sufficient to bring about disorganized mitochondrial networks, reduced aerobic respiration and increased reactive oxygen species. We further show that mutant FUS associates with mitochondria and with mRNAs encoded by the mitochondrial genome. Importantly, similar results were also observed in fibroblasts derived from ALS patients with FUS mutations. Finally, we demonstrate that FUS loss of function does not underlie the observed mitochondrial dysfunction, and also provides a mechanism for the preferential sequestration of the respiratory chain complex mRNAs by FUS that does not involve sequence-specific binding. Together, our data reveal that respiratory chain complex mRNA sequestration underlies the mitochondrial defects characteristic of ALS/FTD and contributes to the FUS toxic gain of function linked to this disease spectrum.
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