title: MicroRNA-15b regulates mitochondrial ROS production and the senescence-associated secretory phenotype through sirtuin 4/SIRT4.
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.
authors.affiliation: Institut für Biochemie und Molekularbiologie II, Universitätsklinikum der Heinrich-Heine-Universität, Düsseldorf, Germany.|Molecular Proteomics Laboratory, BMFZ, Universitätsklinikum der Heinrich-Heine-Universität, Düsseldorf, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Lang
authors.affiliation: IUF - Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Grether-Beck
authors.affiliation: Institut für Biochemie und Molekularbiologie II, Universitätsklinikum der Heinrich-Heine-Universität, Düsseldorf, Germany.
authors.forename: Madhurendra
authors.initials: M
authors.lastname: Singh
authors.affiliation: Institut für Biochemie und Molekularbiologie II, Universitätsklinikum der Heinrich-Heine-Universität, Düsseldorf, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Kuck
authors.affiliation: IUF - Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Jakob
authors.affiliation: Institut für Biochemie und Molekularbiologie II, Universitätsklinikum der Heinrich-Heine-Universität, Düsseldorf, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kefalas
authors.affiliation: Institut für Biochemie und Molekularbiologie II, Universitätsklinikum der Heinrich-Heine-Universität, Düsseldorf, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Altinoluk-Hambüchen
authors.affiliation: Institut für Transplantationsdiagnostik und Zelltherapeutika (ITZ), Düsseldorf, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Graffmann
authors.affiliation: IUF - Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany.
authors.forename: Maren
authors.initials: M
authors.lastname: Schneider
authors.affiliation: Biologisch-Medizinisches Forschungszentrum (BMFZ), Düsseldorf, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Lindecke
authors.affiliation: IUF - Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany.
authors.forename: Heidi
authors.initials: H
authors.lastname: Brenden
authors.affiliation: IUF - Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Felsner
authors.affiliation: Institut für Biochemie und Molekularbiologie II, Universitätsklinikum der Heinrich-Heine-Universität, Düsseldorf, Germany.
authors.forename: Hakima
authors.initials: H
authors.lastname: Ezzahoini
authors.affiliation: IUF - Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Marini
authors.affiliation: Institut für Transplantationsdiagnostik und Zelltherapeutika (ITZ), Düsseldorf, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Weinhold
authors.affiliation: IUF - Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Vierkötter
authors.affiliation: IUF - Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Tigges
authors.affiliation: Institut für Biochemie und Molekularbiologie II, Universitätsklinikum der Heinrich-Heine-Universität, Düsseldorf, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Schmidt
authors.affiliation: Molecular Proteomics Laboratory, BMFZ, Universitätsklinikum der Heinrich-Heine-Universität, Düsseldorf, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Stühler
authors.affiliation: Biologisch-Medizinisches Forschungszentrum (BMFZ), Düsseldorf, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Köhrer
authors.affiliation: Institut für Transplantationsdiagnostik und Zelltherapeutika (ITZ), Düsseldorf, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Uhrberg
authors.affiliation: IUF - Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany.
authors.forename: Judith
authors.initials: J
authors.lastname: Haendeler
authors.affiliation: IUF - Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany.|University of Düsseldorf, Medical Faculty, Düsseldorf, Germany.
authors.forename: Jean
authors.initials: J
authors.lastname: Krutmann
authors.affiliation: Institut für Biochemie und Molekularbiologie II, Universitätsklinikum der Heinrich-Heine-Universität, Düsseldorf, Germany.
authors.forename: Roland P
authors.initials: RP
authors.lastname: Piekorz
mesh_terms: D002478:Cells, Cultured; D016922:Cellular Senescence; D005347:Fibroblasts / Q000378:metabolism* / Q000528:radiation effects; D005720:Gamma Rays; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism* / Q000528:radiation effects; D024101:Mitochondrial Proteins / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D037761:Sirtuins / Q000378:metabolism*; D015595:Skin Aging / Q000502:physiology*; D014466:Ultraviolet Rays
chemical_list: C505361:MIRN15 microRNA, human; D035683:MicroRNAs; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; C525357:SIRT4 protein, human; D037761:Sirtuins
keywords: MicroRNA-15b/miR-15b; SIRT4/Sirtuin 4; nuclear encoded mitochondrial genes; photoaging; reactive oxygen species/ROS; senescence; senescence associated secretory phenotype/SASP; skin