Research Paper Volume 8, Issue 3 pp 484—505

MicroRNA-15b regulates mitochondrial ROS production and the senescence-associated secretory phenotype through sirtuin 4/SIRT4

Alexander Lang1,5, *, , Susanne Grether-Beck2, *, , Madhurendra Singh1, *, , Fabian Kuck1, , Sascha Jakob2, , Andreas Kefalas1, , Simone Altinoluk-Hambüchen1, , Nina Graffmann3, , Maren Schneider2, , Antje Lindecke4, , Heidi Brenden2, , Ingo Felsner2, , Hakima Ezzahoini1, , Alessandra Marini2, , Sandra Weinhold3, , Andrea Vierkötter2, , Julia Tigges2, , Stephan Schmidt1, , Kai Stühler5, , Karl Köhrer4, , Markus Uhrberg3, , Judith Haendeler2, , Jean Krutmann2,6, #, , Roland P. Piekorz1, #, ,

  • 1 Institut für Biochemie und Molekularbiologie II, Universitätsklinikum der Heinrich-Heine-Universität, Düsseldorf, Germany
  • 2 IUF – Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany
  • 3 Institut für Transplantationsdiagnostik und Zelltherapeutika (ITZ), Düsseldorf, Germany
  • 4 Biologisch-Medizinisches Forschungszentrum (BMFZ), Düsseldorf, Germany
  • 5 Molecular Proteomics Laboratory, BMFZ, Universitätsklinikum der Heinrich-Heine-Universität, Düsseldorf, Germany
  • 6 University of Düsseldorf, Medical Faculty, Düsseldorf, Germany
* Shared first authorship
# Shared last authorship

Received: August 5, 2015       Accepted: January 30, 2016       Published: February 26, 2016
How to Cite

Copyright: © 2016 Lang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


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.


CytC: cytochrom C; γIR: gamma-irradiation; GDH: glutamate dehydrogenase; miRNA: microRNA; mitoQ: 10-(6′-ubiquinonyl) decyltriphenylphosphonium bromide; MMP1: matrix metalloproteinase-1; MTCO2: mitochondrially encoded cytochrome C oxidase II; mtSIRT: mitochondrially localized sirtuin; NRF1: nuclear respiratory factor 1; PDH: pyruvate dehydrogenase; qRT-PCR: quantitative real-time PCR; ROS: reactive oxygen species; SASP: senescence associated secretory phenotype; SIRT: sirtuin; TACC3: Transforming Acidic Coiled Coil 3; TFAM: transcription factor A; UTR: untranslated region; UV: ultraviolet; VEGF: vascular endothelial growth factor.