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

Lang, Alexander; Grether-Beck, Susanne; Singh, Madhurendra; Kuck, Fabian; Jakob, Sascha; Kefalas, Andreas; Altinoluk-Hambüchen, Simone; Graffmann, Nina; Schneider, Maren; Lindecke, Antje; Brenden, Heidi; Felsner, Ingo; Ezzahoini, Hakima; Marini, Alessandra; Weinhold, Sandra; Vierkötter, Andrea; Tigges, Julia; Schmidt, Stephan; Stühler, Kai; Köhrer, Karl; Uhrberg, Markus; Haendeler, Judith; Krutmann, Jean; Piekorz, Roland P.

doi:10.18632/aging.100905

Cited by 94 publications

(88 citation statements)

References 105 publications

(129 reference statements)

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“…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).…”

Section: Discussionmentioning

confidence: 99%

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

Zeng

Jiang²,

et al. 2018

Aging Cell

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SIRT4 modulates energy homeostasis in multiple cell types and tissues. However, its role in meiotic oocytes remains unknown. Here, we report that mouse oocytes overexpressing SIRT4 are unable to completely progress through meiosis, showing the inadequate mitochondrial redistribution, lowered ATP content, elevated reactive oxygen species (ROS) level, with the severely disrupted spindle/chromosome organization. Moreover, we find that phosphorylation of Ser293‐PDHE1α mediates the effects of SIRT4 overexpression on metabolic activity and meiotic events in oocytes by performing functional rescue experiments. By chance, we discover the SIRT4 upregulation in oocytes from aged mice; and importantly, the maternal age‐associated deficient phenotypes in oocytes can be partly rescued through the knockdown of SIRT4. These findings reveal the critical role for SIRT4 in the control of energy metabolism and meiotic apparatus during oocyte maturation and indicate that SIRT4 is an essential factor determining oocyte quality.

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Section: Discussionmentioning

confidence: 99%

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

Zeng

Jiang²,

et al. 2018

Aging Cell

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“…In Dicer Δ/Δ CD4 + T cells, the enhanced Nhe1 expression could further result from acidic pHi. According to a recent study, inhibition of miR-15b increases the ROS production, decreases the mitochondrial membrane potential, and modulates mRNA levels of nuclear encoded mitochondrial genes (CytC, TFAM, NRF1) as well as components of the senescence-associated secretory phenotype (IL-6, IL-8, VEGF, MMP1, IL-1-α, IL-1β, and IFN-γ) via Sirtuin4 (SIRT4) [51]. In Dicer Δ/Δ CD4 + T cells, phosphorylation of Akt on both Ser473 and Thr308 after TCR activation is augmented [35].…”

Section: Discussionmentioning

confidence: 99%

Enhanced Reactive Oxygen Species Production, Acidic Cytosolic pH and Upregulated Na+/H+ Exchanger (NHE) in Dicer Deficient CD4+ T Cells

Singh

Zhou²,

Zhang³

et al. 2017

Cell Physiol Biochem

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Background: MicroRNAs (miRNAs) negatively regulate gene expression at a post-transcriptional level. Dicer, a cytoplasmic RNase III enzyme, is required for the maturation of miRNAs from precursor miRNAs. Dicer, therefore, is a critical enzyme involved in the biogenesis and processing of miRNAs. Several biological processes are controlled by miRNAs, including the regulation of T cell development and function. T cells generate reactive oxygen species (ROS) with parallel H⁺ extrusion accomplished by the Na⁺/H⁺-exchanger 1 (NHE1). The present study explored whether ROS production, as well as NHE1 expression and function are sensitive to the lack of Dicer (miRNAs deficient) and could be modified by individual miRNAs. Methods: CD4⁺ T cells were isolated from CD4 specific Dicer deficient (Dicer^Δ/Δ) mice and the respective control mice (Dicer^fl/fl). Transcript and protein levels were quantified with RT-PCR and Western blotting, respectively. For determination of intracellular pH (pHi) cells were incubated with the pH sensitive dye bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein (BCECF) and Na⁺/H⁺ exchanger (NHE) activity was calculated from re-alkalinization after an ammonium pulse. Changes in cell volume were measured using the forward scatter in flow cytometry, and ROS production utilizing 2',7' -dichlorofluorescin diacetate (DCFDA) fluorescence. Transfection of miRNA-control and mimics in T cells was performed using DharmaFECT3 reagent. Results: ROS production, cytosolic H⁺ concentration, NHE1 transcript and protein levels, NHE activity, and cell volume were all significantly higher in CD4⁺ T cells from Dicer^Δ/Δ mice than in CD4⁺ T cells from Dicer^fl/fl mice. Furthermore, individual miR-200b and miR-15b modify pHi and NHE activity in Dicer^fl/fl and Dicer^Δ/Δ CD4⁺ T cells, respectively. Conclusions: Lack of Dicer leads to oxidative stress, cytosolic acidification, upregulated NHE1 expression and activity as well as swelling of CD4⁺ T cells, functions all reversed by miR-15b or miR-200b.

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“…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.…”

Section: Mitochondrial Sirtuins Protect Against Age-related Diseasesmentioning

confidence: 99%

Mitochondrial Sirtuins and Molecular Mechanisms of Aging

Ven

Santos

Haigis

2017

Trends in Molecular Medicine

205

159

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Advancing age is the major risk factor for the development of chronic diseases and is accompanied with changes in metabolic processes and mitochondrial dysfunction. Mitochondrial sirtuins (SIRT3-5) are part of the sirtuin family of NAD+-dependent deacylases and ADP-ribosyl transferases. The dependence on NAD+ links sirtuin enzymatic activity to the metabolic state of the cell, poising them as stress sensors. Recent insights have revealed that SIRT3-5 orchestrate stress responses through coordinated regulation of substrate clusters rather than a few key metabolic enzymes. Additionally, mitochondrial sirtuin function has been implicated in the protection against age-related pathologies including neurodegeneration, cardiopathologies and insulin resistance. In this review, we highlight the molecular targets of SIRT3-5 and discuss their involvement in aging and age-related pathologies.

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

Cited by 94 publications

References 105 publications

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

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

Enhanced Reactive Oxygen Species Production, Acidic Cytosolic pH and Upregulated Na+/H+ Exchanger (NHE) in Dicer Deficient CD4+ T Cells

Mitochondrial Sirtuins and Molecular Mechanisms of Aging

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