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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\n                    <jats:italic>TIMP1<\/jats:italic>\n                    . We also discovered markedly increased skin inflammation that appears to be\u00a0a contributing factor in skin pathology. Histopathologic analyses revealed dysfunctional hair follicles. mtDNA-depleter mice also show changes in expression of aging-associated markers including\n                    <jats:italic>IGF1R<\/jats:italic>\n                    ,\n                    <jats:italic>KLOTHO<\/jats:italic>\n                    ,\n                    <jats:italic>VEGF<\/jats:italic>\n                    , and\n                    <jats:italic>MRPS5<\/jats:italic>\n                    . mtDNA-repleter mice showed that, by turning off the mutant\n                    <jats:italic>POLG1<\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.1038\/s41419-018-0765-9","type":"journal-article","created":{"date-parts":[[2018,6,29]],"date-time":"2018-06-29T10:42:51Z","timestamp":1530268971000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":101,"title":["Reversing wrinkled skin and hair loss in mice by restoring mitochondrial function"],"prefix":"10.1038","volume":"9","author":[{"given":"Bhupendra","family":"Singh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trenton R.","family":"Schoeb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prachi","family":"Bajpai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrzej","family":"Slominski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keshav K.","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,7,20]]},"reference":[{"key":"765_CR1","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1016\/j.mito.2006.11.010","volume":"7","author":"S Alberio","year":"2007","unstructured":"Alberio, S., Mineri, R., Tiranti, V. & Zeviani, M. 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