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

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.

KW - Animals

KW - Autophagy

KW - Calcium

KW - Cells, Cultured

KW - DNA Helicases

KW - DNA Repair Enzymes

KW - Humans

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Mitochondria

KW - Mitochondrial Membrane Transport Proteins

KW - Reactive Oxygen Species

U2 - 10.1084/jem.20111721

DO - 10.1084/jem.20111721

M3 - Journal article

C2 - 22473955

SN - 0022-1007

VL - 209

SP - 855

EP - 869

JO - The Journal of Experimental Medicine

JF - The Journal of Experimental Medicine

IS - 4

ER -