Cockayne syndrome group B protein prevents the accumulation of damaged mitochondria by promoting mitochondrial autophagy

Research output: Contribution to journalJournal articleResearchpeer-review

Morten Scheibye-Knudsen, Mahesh Ramamoorthy, Peter Sykora, Scott Maynard, Ping-Chang Lin, Robin K Minor, David M Wilson, Marcus Cooper, Richard Spencer, Rafael de Cabo, Deborah L Croteau, Vilhelm A Bohr

Cockayne syndrome (CS) is a devastating autosomal recessive disease characterized by neurodegeneration, cachexia, and accelerated aging. 80% of the cases are caused by mutations in the CS complementation group B (CSB) gene known to be involved in DNA repair and transcription. Recent evidence indicates that CSB is present in mitochondria, where it associates with mitochondrial DNA (mtDNA). We report an increase in metabolism in the CSB(m/m) mouse model and CSB-deficient cells. Mitochondrial content is increased in CSB-deficient cells, whereas autophagy is down-regulated, presumably as a result of defects in the recruitment of P62 and mitochondrial ubiquitination. CSB-deficient cells show increased free radical production and an accumulation of damaged mitochondria. Accordingly, treatment with the autophagic stimulators lithium chloride or rapamycin reverses the bioenergetic phenotype of CSB-deficient cells. Our data imply that CSB acts as an mtDNA damage sensor, inducing mitochondrial autophagy in response to stress, and that pharmacological modulators of autophagy are potential treatment options for this accelerated aging phenotype.
Original languageEnglish
JournalThe Journal of Experimental Medicine
Volume209
Issue number4
Pages (from-to)855-69
Number of pages15
DOIs
Publication statusPublished - Apr 2012

    Research areas

  • Animals, Autophagy, Calcium, Cells, Cultured, DNA Helicases, DNA Repair Enzymes, Humans, Male, Mice, Mice, Inbred C57BL, Mitochondria, Mitochondrial Membrane Transport Proteins, Reactive Oxygen Species

ID: 38483520