TY - JOUR
T1 - Cockayne syndrome group B protein prevents the accumulation of damaged mitochondria by promoting mitochondrial autophagy
AU - Scheibye-Knudsen, Morten
AU - Ramamoorthy, Mahesh
AU - Sykora, Peter
AU - Maynard, Scott
AU - Lin, Ping Chang
AU - Minor, Robin K.
AU - Wilson, David M.
AU - Cooper, Marcus
AU - Spencer, Richard
AU - de Cabo, Rafael
AU - Croteau, Deborah L.
AU - Bohr, Vilhelm A.
PY - 2012/4/9
Y1 - 2012/4/9
N2 - 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.
AB - 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.
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U2 - 10.1084/jem.20111721
DO - 10.1084/jem.20111721
M3 - Article
C2 - 22473955
AN - SCOPUS:84861749572
SN - 0022-1007
VL - 209
SP - 855
EP - 869
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 4
ER -