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Telomere Dysfunction Induces Sirtuin Repression that Drives Telomere-Dependent Disease.
- Source :
-
Cell metabolism [Cell Metab] 2019 Jun 04; Vol. 29 (6), pp. 1274-1290.e9. Date of Electronic Publication: 2019 Mar 28. - Publication Year :
- 2019
-
Abstract
- Telomere shortening is associated with stem cell decline, fibrotic disorders, and premature aging through mechanisms that are incompletely understood. Here, we show that telomere shortening in livers of telomerase knockout mice leads to a p53-dependent repression of all seven sirtuins. P53 regulates non-mitochondrial sirtuins (Sirt1, 2, 6, and 7) post-transcriptionally through microRNAs (miR-34a, 26a, and 145), while the mitochondrial sirtuins (Sirt3, 4, and 5) are regulated in a peroxisome proliferator-activated receptor gamma co-activator 1 alpha-/beta-dependent manner at the transcriptional level. Administration of the NAD(+) precursor nicotinamide mononucleotide maintains telomere length, dampens the DNA damage response and p53, improves mitochondrial function, and, functionally, rescues liver fibrosis in a partially Sirt1-dependent manner. These studies establish sirtuins as downstream targets of dysfunctional telomeres and suggest that increasing Sirt1 activity alone or in combination with other sirtuins stabilizes telomeres and mitigates telomere-dependent disorders.<br /> (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Cells, Cultured
Down-Regulation drug effects
Down-Regulation genetics
Embryo, Mammalian
Female
Gene Expression Regulation, Enzymologic drug effects
HEK293 Cells
Humans
Liver drug effects
Liver metabolism
Liver pathology
Liver Cirrhosis pathology
Liver Cirrhosis prevention & control
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mitochondria, Liver drug effects
Mitochondria, Liver metabolism
Nicotinamide Mononucleotide pharmacology
Sirtuin 1 genetics
Sirtuin 1 metabolism
Sirtuins metabolism
Telomerase genetics
Telomerase metabolism
Telomere Homeostasis drug effects
Telomere Homeostasis physiology
Telomere Shortening drug effects
Telomere Shortening genetics
Liver Cirrhosis genetics
Sirtuins genetics
Telomere Shortening physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1932-7420
- Volume :
- 29
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Cell metabolism
- Publication Type :
- Academic Journal
- Accession number :
- 30930169
- Full Text :
- https://doi.org/10.1016/j.cmet.2019.03.001