Journal Article

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

Mitra, Joy, Mitra, Sankar, Kodavati, Manohar, Van Den Bosch, Ludo, Rao, Vikas H. Maloji, Hegde, Muralidhar L., Vedula, Indira, Wang, Haibo, Zhang, Aijun, Hegde, Pavana M., Hamilton, Dale J., Tomkinson, Alan E., Guo, Wenting, Provasek, Vincent

2024

Overview

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. Dysfunction of Fused in Sarcoma (FUS) leads to increased mitochondrial DNA (mtDNA) damage, mutations, and mitochondrial dysfunction. This study shows that FUS collaborates with mtDNA Ligase IIIα to maintain mtDNA repair and integrity.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/100 / 13/106 / 13/109 / 13/51 / 14 / 14/63 / 45 / 45/23 / 631/378/1689 / 631/45/147 / Amyotrophic lateral sclerosis / Autopsies / Autopsy / Damage / DNA damage / DNA repair / FUS gene / FUS protein / Gene expression / Humanities and Social Sciences / Inhibitory postsynaptic potentials / Integrity / Life Sciences / Mitochondrial DNA / Motor neuron diseases / Motor neurone disease / multidisciplinary / Mutants / Mutation / Neurodegenerative diseases / Neurons and Cognition / Pathogenesis / Pluripotency / Sarcoma / Science / Science (multidisciplinary) / Transgenic mice