Cockayne syndrome (CS) is a severe, complex, progressive and autosomal recessive disease characterized by developmental, skeletal, neurological and muscular failure, as well as a premature aging phenotype [1]. Patients with CS can be assigned to two different complementation groups, with the majority carrying mutations in the CSB gene [2]. A clinically identified CSB truncation (CS1AN) has been genetically introduced into a mouse, which displays similar but milder CS phenotypes [3]. The CSB protein plays distinct roles in different DNA repair pathways. It is involved in the transcriptioncoupled repair of UV-induced DNA damage, which is reflected by the sensitivity of human and murine csb m ⁄ m fibroblasts to UV radiation. Furthermore, CSB is involved in the global repair of different types of endogenously formed DNA damage and also participates in regulation of the major nuclear and mitochondrial 8-oxoguanine (8oxoG) Cockayne syndrome (CS) is a complex, progressive disease that involves neurological and developmental impairment and premature aging. The majority of CS patients have mutations in the CSB gene. The CSB protein is involved in multiple DNA repair pathways and CSB mutated cells are sensitive to a broad spectrum of genotoxic agents. We tested the hypothesis that sensitivity to such genotoxins could be mediated by mitochondrial dysfunction as a consequence of the CSB mutation. mtDNA from csb m ⁄ m mice accumulates oxidative damage including 8-oxoguanine, and cells from this mouse are hypersensitive to the mitochondrial oxidant menadione. Inhibitors of mitochondrial complexes and the glycolysis inhibitor 2-deoxyglucose kill csb m ⁄ m cells more efficiently than wild-type cells, via a mechanism that does not correlate with mtDNA damage formation. Menadione depletes cellular ATP, and recovery after depletion is slower in csb m ⁄ m cells. The bioenergetic alteration in csb m ⁄ m cells parallels the simpler organization of supercomplexes consisting of complexes I, III and IV in addition to partially disassembled complex V in the inner mitochondrial membrane. Exposing wild-type cells to DNA intercalating agents induces complex alterations, suggesting a link between mtDNA integrity, respiratory complexes and mitochondrial function. Thus, mitochondrial dysfunction may play a role in the pathology of CS.Abbreviations

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