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 csbm/mmice 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 csbm/mcells 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 csbm/mcells. The bioenergetic alteration in csbm/mcells 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.

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doi.org/10.1111/j.1742-4658.2009.07004.x, hdl.handle.net/1765/24868
The FEBS Journal
Erasmus MC: University Medical Center Rotterdam

Osenbroch, P.O, Auk-Emblem, P, Halsne, R, Strand, J, Forstrøm, R.J, van der Pluijm, I, & Eide, L. (2009). Accumulation of mitochondrial DNA damage and bioenergetic dysfunction in CSB defective cells. The FEBS Journal, 276(10), 2811–2821. doi:10.1111/j.1742-4658.2009.07004.x