Journal
JOURNAL OF INVESTIGATIVE DERMATOLOGY
Volume 138, Issue 1, Pages 132-140Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jid.2017.08.019
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Funding
- Deutsche Forschungsgemeinschaft [Wi 889/6-3, SFB 829 A14, BR2304/9-1, SFB 829 A1, SFB 829 A5, SFB 829 Z2]
- Deutsche Forschungsgemeinschaft (Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases-CECAD)
- Center of Molecular Medicine Cologne of the Medical Faculty (CMMC)
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Accumulation of large-scale mitochondrial DNA (mtDNA) deletions and chronic, subclinical inflammation are concomitant during skin aging, thus raising the question of a causal link. To approach this, we generated mice expressing a mutant mitochondrial helicase (K320E-TWINKLE) in the epidermis to accelerate the accumulation of mtDNA deletions in this skin compartment. Mice displayed low amounts of large-scale deletions and a dramatic depletion of mtDNA in the epidermis and showed macroscopic signs of severe skin inflammation. The mtDNA alterations led to an imbalanced stoichiometry of mitochondrial respiratory chain complexes, inducing a unique combination of cytokine expression, causing a severe inflammatory phenotype, with massive immune cell infiltrates already before birth. Altogether, these data unraveled a previously unknown link between an imbalanced stoichiometry of the mitochondrial respiratory chain complexes and skin inflammation and suggest that severe respiratory chain dysfunction, as observed in few cells leading to a mosaic in aged tissues, might be involved in the development of chronic subclinical inflammation.
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