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.

SIRT4 is essential for metabolic control and meiotic structure during mouse oocyte maturation

“…In this study, we discovered that SIRT4 protein levels are increased in oocytes from old mouse (Figure 7). Likewise, SIRT4 expression is upregulated during senescence triggered by different stimuli in human skin cells and trophoblast stem cells (Castex et al., 2017; Lang et al., 2016). SIRT4 upregulation has also been implicated to adversely impact mitochondrial functions and contribute to the development of senescent phenotypes (Castex et al., 2017).…”

Mitochondrial Sirtuins and Molecular Mechanisms of Aging

“…Likewise, SIRT4 may affect ROS via pyruvate dehydrogenase complex (PDH), glutamate dehydrogenase (GDH) and fatty acid oxidation through malonyl-CoA decarboxylase (MCD) [48–50]. While this will ultimately lead to decreased donation of electrons to the ETC and reduce the production of ROS, recent studies suggest that Sirt4 activity may increase ROS levels in murine cardiomyocytes [51,52]. In sum, decline of sirtuin activity during aging may compromise the signaling function of balanced ROS levels to impair mitochondrial and cellular homeostasis.…”

SASP regulation by noncoding RNA

“…Its high expression in human dermal fibroblasts undergoing replicative or stress-induced senescence was associated to decreased levels of miR-15b [56]. …”