Format

Send to

Choose Destination
Cell Death Dis. 2018 Jul 20;9(7):735. doi: 10.1038/s41419-018-0765-9.

Reversing wrinkled skin and hair loss in mice by restoring mitochondrial function.

Author information

1
Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
2
Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
3
Birmingham Veterans Affairs Medical Center, Birmingham, AL, 35294, USA.
4
Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, 35294, USA. kksingh@uab.edu.
5
Birmingham Veterans Affairs Medical Center, Birmingham, AL, 35294, USA. kksingh@uab.edu.
6
Center for Free Radical Biology, Center for Aging and UAB Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, 35294, USA. kksingh@uab.edu.

Abstract

Mitochondrial DNA (mtDNA) depletion is involved in mtDNA depletion syndromes, mitochondrial diseases, aging and aging-associated chronic diseases, and other human pathologies. To evaluate the consequences of depletion of mtDNA in the whole animal, we created an inducible mtDNA-depleter mouse expressing, in the polymerase domain of POLG1, a dominant-negative mutation to induce depletion of mtDNA in various tissues. These mice showed reduced mtDNA content, reduced mitochondrial gene expression, and instability of supercomplexes involved in oxidative phosphorylation (OXPHOS) resulting in reduced OXPHOS enzymatic activities. We demonstrate that ubiquitous depletion of mtDNA in mice leads to predominant and profound effects on the skin resulting in wrinkles and visual hair loss with an increased number of dysfunctional hair follicles and inflammatory responses. Development of skin wrinkle was associated with the significant epidermal hyperplasia, hyperkeratosis, increased expression of matrix metalloproteinases, and decreased expression of matrix metalloproteinase inhibitor TIMP1. We also discovered markedly increased skin inflammation that appears to be a contributing factor in skin pathology. Histopathologic analyses revealed dysfunctional hair follicles. mtDNA-depleter mice also show changes in expression of aging-associated markers including IGF1R, KLOTHO, VEGF, and MRPS5. mtDNA-repleter mice showed that, by turning off the mutant POLG1 transgene expression, mitochondrial function, as well as the skin and hair pathology, is reversed to wild-type level. To our knowledge that restoration of mitochondrial functions can reverse the skin and hair pathology is unprecedented.

Comment in

PMID:
30026579
PMCID:
PMC6053453
DOI:
10.1038/s41419-018-0765-9
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center