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Targeting the Mitochondrial Phenotype in Cockayne Syndrome Patient Cells: From Bioenergetic Fragility to
Melis Kose1, Elizabeth M McCormick1, Kelsey Keith2
1Mitochondrial Medicine Frontier Program, Division of Genetic and Genomic Medicine, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA.
Biorxiv : the Preprint Server for Biology
|June 3, 2026
Summary
Cockayne syndrome (CS) involves mitochondrial dysfunction, mimicking primary mitochondrial disease (PMD). This study identified five compounds that rescue ATP levels in CS patient cells under stress, offering new therapeutic avenues.
Area of Science:
- Genetics and Molecular Biology
- Cellular Biology
- Mitochondrial Medicine
Background:
- Cockayne syndrome (CS) is a DNA repair disorder often presenting with primary mitochondrial disease (PMD)-like features.
- Mitochondrial DNA depletion and impaired respiratory function are observed in CS, but the cellular mechanisms remain unclear.
- The potential for pharmacological intervention in CS-related mitochondrial dysfunction is an open question.
Purpose of the Study:
- To investigate the mitochondrial phenotype in fibroblasts from Cockayne syndrome patients with ERCC6 variants.
- To screen for therapeutic compounds that can restore cell survival under metabolic stress in CS fibroblasts.
- To elucidate the mechanisms of action for identified therapeutic compounds.
Main Methods:
- Fibroblast characterization included mtDNA content, respiratory chain protein levels, and mitochondrial biogenesis signaling.
- A combined metabolic stress exposure was used to screen 23 candidate compounds for rescuing ATP levels.
- Mechanistic validation involved assessing mitochondrial superoxide, oxidative stress, glutathione, and autophagic flux.
Main Results:
- CS fibroblasts displayed hallmarks of PMD, including reduced mtDNA, decreased Complex I, and impaired mitochondrial respiration.
- Under metabolic stress, ATP levels in CS fibroblasts collapsed significantly compared to controls.
- Five compounds (NAC, CoQ10, rapamycin, taurine, (-)-epicatechin) restored ATP-based cell survival, acting via ROS reduction, mTORC1 inhibition, or enhanced stress resilience.
Conclusions:
- ERCC6 deficiency causes a complex, stress-sensitive mitochondrial phenotype in CS patients.
- Pharmacological targeting of distinct pathways, including oxidative stress reduction and autophagy modulation, can treat this phenotype.
- These findings support advancing novel therapeutic strategies for CSB patients into clinical trials.
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