FUS unveiled in mitochondrial DNA repair and targeted ligase-1 expression rescues repair-defects in FUS-linked motor neuron disease
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 recruit...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-03-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-45978-6 |
| _version_ | 1827321369596002304 |
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| author | 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 Van Den Bosch Muralidhar L. Hegde |
| author_facet | 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 Van Den Bosch Muralidhar L. Hegde |
| author_sort | Manohar Kodavati |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-25T01:05:02Z |
| format | Article |
| id | doaj.art-84695b5aec76489b85b86bbc091bf336 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-04-25T01:05:02Z |
| publishDate | 2024-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-84695b5aec76489b85b86bbc091bf3362024-03-10T12:17:55ZengNature PortfolioNature Communications2041-17232024-03-0115111610.1038/s41467-024-45978-6FUS unveiled in mitochondrial DNA repair and targeted ligase-1 expression rescues repair-defects in FUS-linked motor neuron diseaseManohar Kodavati0Haibo Wang1Wenting Guo2Joy Mitra3Pavana M. Hegde4Vincent Provasek5Vikas H. Maloji Rao6Indira Vedula7Aijun Zhang8Sankar Mitra9Alan E. Tomkinson10Dale J. Hamilton11Ludo Van Den Bosch12Muralidhar L. Hegde13Division of DNA Repair Research within the Center for Neuroregeneration, Department of Neurosurgery, Houston Methodist Research InstituteDivision of DNA Repair Research within the Center for Neuroregeneration, Department of Neurosurgery, Houston Methodist Research InstituteKU Leuven-Department of Neurosciences, Experimental Neurology and Leuven Brain Institute (LBI)Division of DNA Repair Research within the Center for Neuroregeneration, Department of Neurosurgery, Houston Methodist Research InstituteDivision of DNA Repair Research within the Center for Neuroregeneration, Department of Neurosurgery, Houston Methodist Research InstituteDivision of DNA Repair Research within the Center for Neuroregeneration, Department of Neurosurgery, Houston Methodist Research InstituteDivision of DNA Repair Research within the Center for Neuroregeneration, Department of Neurosurgery, Houston Methodist Research InstituteCenter for Bioenergetics, Houston Methodist Research InstituteCenter for Bioenergetics, Houston Methodist Research InstituteDivision of DNA Repair Research within the Center for Neuroregeneration, Department of Neurosurgery, Houston Methodist Research InstituteDepartments of Internal Medicine, and Molecular Genetics and Microbiology and University of New Mexico Comprehensive Cancer Center, University of New MexicoCenter for Bioenergetics, Houston Methodist Research InstituteKU Leuven-Department of Neurosciences, Experimental Neurology and Leuven Brain Institute (LBI)Division of DNA Repair Research within the Center for Neuroregeneration, Department of Neurosurgery, Houston Methodist Research InstituteAbstract 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.https://doi.org/10.1038/s41467-024-45978-6 |
| spellingShingle | 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 Van Den Bosch Muralidhar L. Hegde FUS unveiled in mitochondrial DNA repair and targeted ligase-1 expression rescues repair-defects in FUS-linked motor neuron disease Nature Communications |
| title | FUS unveiled in mitochondrial DNA repair and targeted ligase-1 expression rescues repair-defects in FUS-linked motor neuron disease |
| title_full | FUS unveiled in mitochondrial DNA repair and targeted ligase-1 expression rescues repair-defects in FUS-linked motor neuron disease |
| title_fullStr | FUS unveiled in mitochondrial DNA repair and targeted ligase-1 expression rescues repair-defects in FUS-linked motor neuron disease |
| title_full_unstemmed | FUS unveiled in mitochondrial DNA repair and targeted ligase-1 expression rescues repair-defects in FUS-linked motor neuron disease |
| title_short | FUS unveiled in mitochondrial DNA repair and targeted ligase-1 expression rescues repair-defects in FUS-linked motor neuron disease |
| title_sort | fus unveiled in mitochondrial dna repair and targeted ligase 1 expression rescues repair defects in fus linked motor neuron disease |
| url | https://doi.org/10.1038/s41467-024-45978-6 |
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