Reversing wrinkled skin and hair loss in mice by restoring mitochondrial function.
Reversing wrinkled skin and hair loss in mice by restoring mitochondrial function.
复制标题
DOI：
10.1038/s41419-018-0765-9
复制
发表时间：
2018-07-20
影响因子：
9
通讯作者：
Singh KK
中科院分区：
文献类型：
--
作者：
Singh B;Schoeb TR;Bajpai P;Slominski A;Singh KK
线粒体DNA（mtDNA）缺失涉及mtDNA缺失综合征、线粒体疾病、衰老和衰老相关慢性疾病以及其他人类病理学。为了评估整个动物中mtDNA耗竭的后果，我们创建了一个诱导型mtDNA耗竭小鼠，在POLG 1的聚合酶结构域中表达显性负突变，以诱导各种组织中mtDNA的耗竭。这些小鼠表现出线粒体DNA含量降低、线粒体基因表达降低以及参与氧化磷酸化（OXPHOS）的超复合物的不稳定性，导致OXPHOS酶活性降低。我们证明，小鼠中mtDNA的普遍缺失导致对皮肤的显著和深远的影响，导致皱纹和可见的脱发，以及功能失调的毛囊和炎症反应的数量增加。皮肤皱纹的发生与表皮明显增生、角化过度、基质金属蛋白酶表达增加和基质金属蛋白酶抑制剂TIMP 1表达减少有关。我们还发现皮肤炎症明显增加，这似乎是皮肤病理学的一个促成因素。组织学分析显示毛囊功能障碍。mtDNA耗竭小鼠也显示出衰老相关标志物表达的变化，包括IGF1R、KLOTHO、VEGF和MRPS5。mtDNA补充小鼠表明，通过关闭突变POLG 1转基因表达，线粒体功能以及皮肤和毛发病理学被逆转到野生型水平。据我们所知，线粒体功能的恢复可以逆转皮肤和毛发病理是前所未有的。
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.
登录
查看更多内容
影响因子：
3.7
作者：
Bonomi M;Somigliana E;Cacciatore C;Busnelli M;Rossetti R;Bonetti S;Paffoni A;Mari D;Ragni G;Persani L;Italian Network for the study of Ovarian Dysfunctions
通讯作者：
Italian Network for the study of Ovarian Dysfunctions
影响因子：
10.3
作者：
Bosset, S;Bonnet-Duquennoy, M;Nicolas, JF
通讯作者：
Nicolas, JF
影响因子：
11.2
作者：
Brierley, EJ;Johnson, MA;Turnbull, DM
通讯作者：
Turnbull, DM
影响因子：
3.8
作者：
Cho, Young-Suk;Kim, Chan-Hyung;Park, Jong-Wan
通讯作者：
Park, Jong-Wan
影响因子：
168.9
作者：
Lahmann, C;Bergemann, J;Young, AR
通讯作者：
Young, AR