FUS unveiled in mitochondrial DNA repair and targeted ligase-1 expression rescues repair-defects in FUS-linked motor neuron disease

Manohar Kodavati, Haibo Wang, Wenting Guo, Joy Mitra, Pavana M. Hegde, Vincent Provasek, Vikas H. Maloji Rao, Indira Vedula, Aijun Zhang, Sankar Mitra, Alan E. Tomkinson, Dale J. Hamilton, Ludo Bosch and Muralidhar L. Hegde ()
Additional contact information
Manohar Kodavati: Houston Methodist Research Institute
Haibo Wang: Houston Methodist Research Institute
Wenting Guo: Experimental Neurology and Leuven Brain Institute (LBI)
Joy Mitra: Houston Methodist Research Institute
Pavana M. Hegde: Houston Methodist Research Institute
Vincent Provasek: Houston Methodist Research Institute
Vikas H. Maloji Rao: Houston Methodist Research Institute
Indira Vedula: Houston Methodist Research Institute
Aijun Zhang: Houston Methodist Research Institute
Sankar Mitra: Houston Methodist Research Institute
Alan E. Tomkinson: and Molecular Genetics and Microbiology and University of New Mexico Comprehensive Cancer Center, University of New Mexico
Dale J. Hamilton: Houston Methodist Research Institute
Ludo Bosch: Experimental Neurology and Leuven Brain Institute (LBI)
Muralidhar L. Hegde: Houston Methodist Research Institute

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-45978-6

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