Proteins of nucleotide and base excision repair pathways interact in mitochondria to protect from loss of subcutaneous fat, a hallmark of aging

York Kamenisch, Maria Fousteri, Jennifer Knoch, Anna Katharina Von Thaler, Birgit Fehrenbacher, Hiroki Kato, Thomas Becker, Martijn E.T. Dollé, Raoul Kuiper, Marc Majora, Martin Schaller, Gijsbertus T.J. Van Der Horst, Harry Van Steeg, Martin Röcken, Doron Rapaport, Jean Krutmann, Leon H. Mullenders, Mark Berneburg

Research output: Contribution to journalArticlepeer-review

108 Citations (Scopus)

Abstract

Defects in the DNA repair mechanism nucleotide excision repair (NER) may lead to tumors in xeroderma pigmentosum (XP) or to premature aging with loss of subcutaneous fat in Cockayne syndrome (CS). Mutations of mitochondrial (mt)DNA play a role in aging, but a link between the NER-associated CS proteins and base excision repair (BER)-associated proteins in mitochondrial aging remains enigmatic. We show functional increase of CSA and CSB inside mt and complex formation with mtDNA, mt human 8-oxoguanine glycosylase (mtOGG)-1, and mt single-stranded DNA binding protein (mtSSBP)-1 upon oxidative stress. MtDNA mutations are highly increased in cells from CS patients and in subcutaneous fat of aged Csbm/m and Csa-/- mice. Thus, the NER-proteins CSA and CSB localize to mt and directly interact with BER-associated human mitochondrial 8-oxoguanine glycosylase-1 to protect from aging- and stress-induced mtDNA mutations and apoptosis-mediated loss of subcutaneous fat, a hallmark of aging found in animal models, human progeroid syndromes like CS and in normal human aging.

Original languageEnglish
Pages (from-to)379-390
Number of pages12
JournalJournal of Experimental Medicine
Volume207
Issue number2
DOIs
Publication statusPublished - Feb 15 2010
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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