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

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

Research output: Contribution to journalArticle

107 Citations (Scopus)

Abstract

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 (US)
Pages (from-to)855-869
Number of pages15
JournalJournal of Experimental Medicine
Volume209
Issue number4
DOIs
StatePublished - Apr 9 2012
Externally publishedYes

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Cockayne Syndrome
Autophagy
Mitochondria
Mitochondrial DNA
Proteins
Lithium Chloride
Phenotype
Cachexia
Ubiquitination
Sirolimus
DNA Repair
Energy Metabolism
DNA Damage
Free Radicals
Pharmacology
Mutation
Genes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Scheibye-Knudsen, M., Ramamoorthy, M., Sykora, P., Maynard, S., Lin, P-C., Minor, R. K., ... Bohr, V. A. (2012). Cockayne syndrome group B protein prevents the accumulation of damaged mitochondria by promoting mitochondrial autophagy. Journal of Experimental Medicine, 209(4), 855-869. https://doi.org/10.1084/jem.20111721

Cockayne syndrome group B protein prevents the accumulation of damaged mitochondria by promoting mitochondrial autophagy. / Scheibye-Knudsen, Morten; Ramamoorthy, Mahesh; Sykora, Peter; Maynard, Scott; Lin, Ping-Chang; Minor, Robin K.; Wilson, David M.; Cooper, Marcus; Spencer, Richard; de Cabo, Rafael; Croteau, Deborah L.; Bohr, Vilhelm A.

In: Journal of Experimental Medicine, Vol. 209, No. 4, 09.04.2012, p. 855-869.

Research output: Contribution to journalArticle

Scheibye-Knudsen, M, Ramamoorthy, M, Sykora, P, Maynard, S, Lin, P-C, Minor, RK, Wilson, DM, Cooper, M, Spencer, R, de Cabo, R, Croteau, DL & Bohr, VA 2012, 'Cockayne syndrome group B protein prevents the accumulation of damaged mitochondria by promoting mitochondrial autophagy', Journal of Experimental Medicine, vol. 209, no. 4, pp. 855-869. https://doi.org/10.1084/jem.20111721
Scheibye-Knudsen, Morten ; Ramamoorthy, Mahesh ; Sykora, Peter ; Maynard, Scott ; Lin, Ping-Chang ; Minor, Robin K. ; Wilson, David M. ; Cooper, Marcus ; Spencer, Richard ; de Cabo, Rafael ; Croteau, Deborah L. ; Bohr, Vilhelm A. / Cockayne syndrome group B protein prevents the accumulation of damaged mitochondria by promoting mitochondrial autophagy. In: Journal of Experimental Medicine. 2012 ; Vol. 209, No. 4. pp. 855-869.
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