bioRxiv : the preprint server for biologyJun 3, 2026

Improving Energy Problems in Cockayne Syndrome Patient Cells with Drug Treatment

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Jun 4, 2026

Abstract

Fibroblasts from patients with Cockayne syndrome showed ATP levels collapsing to approximately 20% of controls under metabolic stress.

Reduced mitochondrial DNA content and decreased expression of a key respiratory chain protein were observed in patient fibroblasts.
Increased levels of a protein associated with mitochondrial import were found alongside decreased expression of a factor involved in mitochondrial biogenesis.
Five compounds were identified that restored ATP-based survival in patient fibroblasts during stress exposure.
Mechanistic profiling indicated three functional classes of therapeutic effects related to oxidative stress reduction, autophagy modulation, and improved cellular resilience.
These findings suggest that targeting specific pathways may offer pharmacological treatment options for Cockayne syndrome.

Simplified

BACKGROUND: Cockayne syndrome (CS), primarily caused by autosomal recessive pathogenic variants in(CSB) or(CSA), is a transcription-coupled nucleotide excision repair disorder. CS frequently presents with features similar to primary mitochondrial disease (PMD), including leukodystrophy, lactic acidemia, and skeletal muscle mitochondrial DNA (mtDNA) depletion. How this mitochondrial phenotype arises at the cellular level, and whether it can be pharmacologically targeted, is not yet clear. ERCC6ERCC8

METHODS: We characterized mtDNA content, respiratory chain (RC) protein abundance, mitochondrial biogenesis signaling pathways, and oxidative phosphorylation capacity in primary fibroblasts from two siblings with identical compound heterozygouspathogenic variants (c.1526+1G>T; c.2800C>A, p.Pro934Thr) despite marked intrafamilial phenotypic divergence. A combined metabolic stress exposure (galactose, reduced glutamine, and buthionine sulfoximine, (BSO)) which reduced CS cell survival was used to screen for therapeutic leads among twenty-three candidate mitochondrial disease therapeutic compounds. Lead compounds were mechanistically validated at the level of mitochondrial superoxide, total cellular oxidative stress, glutathione, and autophagic flux. ERCC6

RESULTS: Patient fibroblasts exhibited several hallmarks of PMD, including reduced mtDNA content, decreased expression of complex I subunit NDUFB8, elevated expression of TOM20 with paradoxically decreased PGC1α suggestive of impaired mitophagic clearance, and decreased mitochondrial respiratory capacity. Under combined metabolic stress, ATP-levels indicative of survival in CS patient fibroblasts selectively collapsed to ∼20% of controls. Five dual-rescue compounds, defined as agents that reproducibly restored ATP-based cell survival in both patient fibroblast lines under stress, were identified, including-acetylcysteine (NAC), coenzyme Q10 (CoQ10), rapamycin, taurine, and (-)-epicatechin. Mechanistic profiling resolved three functional classes of therapeutic effects in CS cells: (1) upstream mitochondrial reactive oxygen species reduction (NAC, CoQ10); (2) mTORC1 inhibition bypassing defective stress-induced autophagic induction (rapamycin); and (3) extra-mitochondrial improvement in cellular stress resilience ((-)- epicatechin, taurine). N

CONCLUSIONS: -based CSB deficiency produced a stress-sensitive and physiologically complex mitochondrial phenotype in patient fibroblasts that was pharmacologically treatable by targeting three mechanistically distinct pathways. Oxidative and broader stress buffering, autophagy modulation via mTORC1 inhibition, and enhanced cellular resilience highlight novel therapeutic opportunities to be advanced to clinical trials in CSB patients. ERCC6

Funding

Competing interests

Conflict of Interest. MJF is a named inventor or co-inventor on multiple patent filings by the Children’s Hospital of Philadelphia related to mitochondrial disease therapies and/or diagnostics, and is engaged with companies involved in mitochondrial disease therapeutic preclinical and/or clinical-stage development. MJF is co-founder of Rarefy Therapeutics LLC; founder of M-Vortex LLC; advisory board member with equity interest in RiboNova Inc.; scientific advisory board member and paid consultant with Khondrion and Larimar Therapeutics; has served as a paid consultant for Ajinomoto-Cambrooke, Astellas (formerly Mitobridge), BPGbio (with equity interest), Casma Therapeutics, Cyclerion Therapeutics, Epirium Bio (formerly Cardero Therapeutics), HealthCap VII Advisor AB, Imel Therapeutics, Mayflower, Inc., Primera Therapeutics, Inc., Minovia Therapeutics, Mission Therapeutics, NeuroVive Pharmaceutical AB, Precision Biosciences, Reneo Therapeutics, Saol Therapeutics, Sironax, Stealth BioTherapeutics, Vincere Bio, and Zogenix; and/or has been a sponsored research collaborator for Aadi Bioscience, Adjuvia Therapeutics, Astellas, Cyclerion Therapeutics, Epirium Bio, Imel Therapeutics, Khondrion, Merck, Minovia Therapeutics, Mission Therapeutics, NeuroVive Pharmaceutical AB, Precision Biosciences, Pretzel Therapeutics, PTC Therapeutics, Raptor Pharmaceuticals, REATA Inc., Reneo Therapeutics, RiboNova, Saol Therapeutics, Standigm, Stealth BioTherapeutics, and Thiogenesis. MJF also has received speaker payments from Chemistry Rx and royalty payments from Elsevier. The other authors have no relevant conflicts of interest to declare.

PubMed

Improving Energy Problems in Cockayne Syndrome Patient Cells with Drug Treatment

Abstract

Funding

Competing interests

You found one interesting study. We’ll send the next 7.

What Lands in Your Inbox Each Week:

Recent issues from the longevity & aging brief

Abstract

Funding

Competing interests

Related papers

You found one interesting study. We’ll send the next 7.

What Lands in Your Inbox Each Week:

Recent issues from the longevity & aging brief