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CSB (red) moved into mitochondria (blue) after oxidative stress.

Mutations underlying a rare disorder in which children rapidly age disrupt mitochondrial DNA repair, show Kamenisch and colleagues. Faulty repair leads to an accumulation of mutations in mitochondrial DNA, a molecular hallmark of growing old.

Recent studies have connected the excess of mitochondrial gene mutations to signs of aging, including hair loss, bone loss, and the loss of subcutaneous fat. The early aging disorder, Cockayne syndrome (CS), is also marked by fat loss, along with sensitivity to UV radiation, which reflects faulty DNA repair. CS patients bear defects in the nucleotide excision repair (NER) pathway, which until now was only known to act on nuclear DNA. Here, Kamenisch and colleagues discover that NER proteins rush into the mitochondria during times of oxidative stress.

When the defective NER proteins that characterize CS—CSA and CSB—entered mitochondria after irradiation, errors accumulated rapidly during mitochondrial DNA replication in cultured cells from CS patients. CSA and CSB interacted with mitochondrial proteins in the base excision DNA repair pathway, which normally removes oxidative damage. The authors speculate that interactions between NER proteins and base excision proteins form a reparative complex; however, the details of that proposed network remain elusive. How CSA and CSB enter the mitochondria in times of stress remains to be investigated as well.

A buildup of mitochondrial gene mutations could be responsible for the subcutaneous fat loss characteristic of CS, suggest the authors. Indeed, the subcutaneous fat of adult, irradiated mice lacking CSA and CSB was teeming with mitochondrial DNA mutations. And fat cells with many mutations often died, reducing the overall number of fat cells in the mice.


Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press