Accumulation of mitochondrial DNA damage and bioenergetic dysfunction in CSB defective cells

Pia O. Osenbroch, Pia Auk-Emblem, Ruth Halsne, Janne Strand, Rune J. Forstrøm, Ingrid Van Der Pluijm, Lars Eide*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

52 Citations (Scopus)


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/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 csbm/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 csbm/m cells. The bioenergetic alteration in csbm/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.

Original languageEnglish
Pages (from-to)2811-2821
Number of pages11
JournalFEBS Journal
Issue number10
Publication statusPublished - May 2009


Dive into the research topics of 'Accumulation of mitochondrial DNA damage and bioenergetic dysfunction in CSB defective cells'. Together they form a unique fingerprint.

Cite this