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    Mutations in RNASEH1 and Twinkle cause distinct mitochondrial DNA releases, activating innate immunity in Chronic Progressive External Ophthalmoplegia (CPEO). This explains disease heterogeneity and suggests targeted therapies for primary mitochondrial disorders (PMDs).

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    Area of Science:

    • Mitochondrial Biology and Genetics
    • Immunology and Inflammation
    • Neuroscience and Neurological Disorders

    Background:

    • Chronic Progressive External Ophthalmoplegia (CPEO) is a primary mitochondrial disorder (PMD) linked to nuclear gene mutations affecting mitochondrial DNA (mtDNA) maintenance.
    • CPEO presents with ocular/muscular symptoms but can progress to CPEO-plus with neurological complications, a transition poorly understood.
    • Innate immune activation via released mitochondrial nucleic acids is increasingly recognized as a key disease modifier in PMDs.

    Purpose of the Study:

    • To investigate how mutations in RNASEH1 and Twinkle genes contribute to innate immune activation in CPEO.
    • To differentiate the specific mitochondrial nucleic acids released by RNASEH1 versus Twinkle mutations.
    • To explore the implications of these pathways on microglial activation and potential therapeutic targets.

    Main Methods:

    • Utilized patient-derived fibroblasts with mutations in RNASEH1, Twinkle, or both.
    • Analyzed the release of mitochondrial DNA (mtDNA) and mitochondrial double-stranded RNA (mt-dsRNA) into the cytosol.
    • Assessed the impact of POLRMT and STING inhibitors (IMT-1 and H-151) on immune gene expression.
    • Investigated cytosolic sensing-triggered paracrine signaling to microglia.

    Main Results:

    • RNASEH1 mutations caused mt-dsRNA release, while Twinkle mutations led to mtDNA release, with distinct cytosolic nucleic acid profiles.
    • Inhibitors targeting POLRMT and STING modulated interferon-stimulated gene expression downstream of RNASEH1 and Twinkle mutations, respectively.
    • A compound mutation line released both mt-dsRNA and mtDNA, engaging multiple inflammatory pathways simultaneously.
    • Cytosolic sensing activated bystander microglia via paracrine signaling, suggesting a link to neurological progression.

    Conclusions:

    • RNASEH1 and Twinkle mutations differentially drive innate immune activation in CPEO through distinct mitochondrial nucleic acid release.
    • Innate immunity is a common feature of mtDNA instability, with mutations engaging specific sensing pathways.
    • Findings support precision medicine strategies targeting distinct innate immune pathways for heterogeneous PMDs like CPEO.