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FUS unveiled in mitochondrial DNA repair and targeted ligase-1 expression rescues repair-defects in FUS-linked motor
Manohar Kodavati1, Haibo Wang1, Wenting Guo2,3,4
1Division of DNA Repair Research within the Center for Neuroregeneration, Department of Neurosurgery, Houston Methodist Research Institute, Houston, TX, USA.
Abstract:
This study establishes the physiological role of Fused in Sarcoma (FUS) in mitochondrial DNA (mtDNA) repair and highlights its implications to the pathogenesis of FUS-associated neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). Endogenous FUS interacts with and recruits mtDNA Ligase IIIα (mtLig3) to DNA damage sites within mitochondria, a relationship essential for maintaining mtDNA repair and integrity in healthy cells. Using ALS patient-derived FUS mutant cell lines, a transgenic mouse model, and human autopsy samples, we discovered that compromised FUS functionality hinders mtLig3's repair role, resulting in increased mtDNA damage and mutations. These alterations cause various manifestations of mitochondrial dysfunction, particularly under stress conditions relevant to disease pathology. Importantly, rectifying FUS mutations in patient-derived induced pluripotent cells (iPSCs) preserves mtDNA integrity. Similarly, targeted introduction of human DNA Ligase 1 restores repair mechanisms and mitochondrial activity in FUS mutant cells, suggesting a potential therapeutic approach. Our findings unveil FUS's critical role in mitochondrial health and mtDNA repair, offering valuable insights into the mechanisms underlying mitochondrial dysfunction in FUS-associated motor neuron disease.
Insights
Fused in Sarcoma (FUS) protein is crucial for repairing mitochondrial DNA (mtDNA) damage. Impaired FUS function leads to mtDNA mutations and dysfunction, contributing to neurodegenerative diseases like ALS.
Area of Science:
- Molecular Biology
- Neuroscience
- Genetics
Background:
- Fused in Sarcoma (FUS) protein's role in cellular processes is increasingly recognized.
- Mitochondrial DNA (mtDNA) integrity is vital for cellular function and linked to neurodegeneration.
- Dysfunctional mitochondria are implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS).
Purpose of the Study:
- To elucidate the physiological role of FUS in mitochondrial DNA (mtDNA) repair.
- To investigate the link between FUS dysfunction, mtDNA repair, and FUS-associated neurodegenerative diseases, including ALS.
Main Methods:
- Investigated endogenous FUS interaction with mtDNA Ligase IIIα (mtLig3) at mitochondrial DNA damage sites.
- Utilized ALS patient-derived FUS mutant cell lines, transgenic mouse models, and human autopsy samples.
- Employed induced pluripotent stem cells (iPSCs) derived from ALS patients to assess mutation rectification and therapeutic interventions.
Main Results:
- Endogenous FUS recruits mtLig3 to repair mitochondrial DNA damage, maintaining mtDNA integrity.
- Compromised FUS function impairs mtLig3's repair activity, leading to elevated mtDNA damage and mutations.
- Mitochondrial dysfunction, particularly under stress, is observed in FUS-mutant models.
- Rectifying FUS mutations in patient iPSCs restored mtDNA integrity.
- Introducing human DNA Ligase 1 rescued repair mechanisms and mitochondrial activity in FUS mutant cells.
Conclusions:
- FUS plays a critical physiological role in the maintenance and repair of mitochondrial DNA.
- Defects in FUS function contribute to mtDNA damage and mitochondrial dysfunction, underlying FUS-associated neurodegenerative diseases like ALS.
- Targeting FUS-mediated repair pathways presents a potential therapeutic strategy for FUS-associated motor neuron diseases.
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