MicroRNA-15b regulates mitochondrial ROS production and the senescence-associated secretory phenotype through sirtuin 4/SIRT4.
Aging (Albany NY), 2016/3;8(3):484-505.
Lang A[1, 2], Grether-Beck S[3], Singh M[1], Kuck F[1], Jakob S[3], Kefalas A[1], Altinoluk-Hambüchen S[1], Graffmann N[4], Schneider M[3], Lindecke A[5], Brenden H[3], Felsner I[3], Ezzahoini H[1], Marini A[3], Weinhold S[4], Vierkötter A[3], Tigges J[3], Schmidt S[1], Stühler K[2], Köhrer K[5], Uhrberg M[4], Haendeler J[3], Krutmann J[3, 6], Piekorz RP[1]
Affiliations
PMID: 26959556
Abstract
Mammalian sirtuins are involved in the control of metabolism and life-span regulation. Here, we link the mitochondrial sirtuin SIRT4 with cellular senescence, skin aging, and mitochondrial dysfunction. SIRT4 expression significantly increased in human dermal fibroblasts undergoing replicative or stress-induced senescence triggered by UVB or gamma-irradiation. In-vivo, SIRT4 mRNA levels were upregulated in photoaged vs. non-photoaged human skin. Interestingly, in all models of cellular senescence and in photoaged skin, upregulation of SIRT4 expression was associated with decreased levels of miR-15b. The latter was causally linked to increased SIRT4 expression because miR-15b targets a functional binding site in the SIRT4 gene and transfection of oligonucleotides mimicking miR-15b function prevented SIRT4 upregulation in senescent cells. Importantly, increased SIRT4 negatively impacted on mitochondrial functions and contributed to the development of a senescent phenotype. Accordingly, we observed that inhibition of miR-15b, in a SIRT4-dependent manner, increased generation of mitochondrial reactive oxygen species, decreased mitochondrial membrane potential, and modulated mRNA levels of nuclear encoded mitochondrial genes and components of the senescence-associated secretory phenotype (SASP). Thus, miR-15b is a negative regulator of stress-induced SIRT4 expression thereby counteracting senescence associated mitochondrial dysfunction and regulating the SASP and possibly organ aging, such as photoaging of human skin.
Keywords: MicroRNA-15b/miR-15b; SIRT4/Sirtuin 4; nuclear encoded mitochondrial genes; photoaging; reactive oxygen species/ROS; senescence; senescence associated secretory phenotype/SASP; skin
MeSH terms
Cells, Cultured; Cellular Senescence; Fibroblasts; Gamma Rays; Humans; Male; MicroRNAs; Mitochondria; Mitochondrial Proteins; Reactive Oxygen Species; Sirtuins; Skin Aging; Ultraviolet Rays
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