title: Cockayne syndrome group B protein prevents the accumulation of damaged mitochondria by promoting mitochondrial autophagy.
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.
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Morten
authors.initials: M
authors.lastname: Scheibye-Knudsen
authors.forename: Mahesh
authors.initials: M
authors.lastname: Ramamoorthy
authors.forename: Peter
authors.initials: P
authors.lastname: Sykora
authors.forename: Scott
authors.initials: S
authors.lastname: Maynard
authors.forename: Ping-Chang
authors.initials: PC
authors.lastname: Lin
authors.forename: Robin K
authors.initials: RK
authors.lastname: Minor
authors.forename: David M
authors.initials: DM
authors.lastname: Wilson
authors.forename: Marcus
authors.initials: M
authors.lastname: Cooper
authors.forename: Richard
authors.initials: R
authors.lastname: Spencer
authors.forename: Rafael
authors.initials: R
authors.lastname: de Cabo
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Croteau
authors.forename: Vilhelm A
authors.initials: VA
authors.lastname: Bohr
mesh_terms: D000818:Animals; D001343:Autophagy; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004265:DNA Helicases / Q000502:physiology*; D045643:DNA Repair Enzymes / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D000075223:Poly-ADP-Ribose Binding Proteins; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D000075223:Poly-ADP-Ribose Binding Proteins; D017382:Reactive Oxygen Species; D004265:DNA Helicases; C078673:ERCC6 protein, human; D045643:DNA Repair Enzymes; D002118:Calcium