Reversing age-related phenotypic changes in mice with mitochondrial DNA depletion

Reversing wrinkled and hairless skin in mice

Many mitochondrial diseases are associated with mitochondrial dysfunction, the majority of which is due to dysfunctional mitochondrial mitochondrial oxidative-phosphorylation. Mitochondrial OXPHOS is responsible for the majority of cellular adenosine Triphosphate (ATP). OXPHOS functions are largely dependent on the coordinated expressions of proteins encoded in both the mitochondrial and nuclear genomes. The mitochondrial genome of humans encodes 13 polypeptides, while the nuclear genome encodes more than 85 polypeptides that are required to assemble the OXPHOS. Depletion of mitochondrial DNA (mtDNA), which is a component of OXPHOS, can lead to mtDNA syndromes. MDSs is a group of heterogeneous disorders characterized by low levels of mtDNA in specific tissues. In various target organs, mtDNA loss leads to pathological changes. MDS results from the genetic defects in the nuclear-encoded genes that participate in mtDNA replication, and mitochondrial nucleotide metabolism and nucleotide salvage pathway1, 4,5,6,7,8,9,10. mtDNA depletion is also implicated in other human diseases such as mitochondrial diseases, cardiovascular11, 12, diabetes13,14,15, age-associated neurological disorders16,17,18, and cancer19,20,21,22,23,24,25.

A general decline in mitochondrial function has been extensively reported during aging26,27,28,29,30,31,32,33. Further, mitochondrial dysfunction has been shown to be the driving force behind age-related diseases in humans16,17.18. 34.35.36. The mtDNA of mice that are prone to premature aging is elevated37,38. Studies have also shown that mtDNA mutations are not the only factor affecting aging. There is a notable age-related depletion of mtDNA in several tissues40,41.42. Women with premature ovarian ageing also show a depletion of mtDNA43. Low mtDNA copies are associated with frailty, and in a multi-ethnic population is also a predictor for all-cause mortality44. Recent research revealed that on average, humans lose four copies of their mtDNA each decade. This study found that a decrease in the mtDNA copies was associated with age-related physical parameters39.

In order to better understand the role of mtDNA loss in aging, we created a mouse that expresses a dominant negative (DN) mutation in the POLG1 polymerase domain. This mutation causes mtDNA degradation in the entire animal. Skin wrinkles and hair loss were the most prominent phenotypic change observed in these mice. In this study, we show that the phenotypic effects of mtDNA-induced depletion can be reversed through restoration of mitochondrial functions upon replacement of mtDNA.

Source:
https://www.nature.com/articles/s41419-018-0765-9

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