Dual Mode of Mitochondrial ROS Action during Reprogramming to Pluripotency

Skvortsova, Elena V.; Nazarov, Igor; Tomilin, Alexey; Sinenko, Sergey

doi:10.3390/ijms231810924

Cited by 8 publications

(16 citation statements)

References 55 publications

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“…This deficit leads to the accumulation of ROS in mitochondria, which can cause damage to macromolecules and induce the release of ROS from the mitochondria into the cytosol, resulting in cellular senescence. 60,81,82 Consistent with these findings, our study showed that SOD2 expression was reduced and that cellular senescence was increased in BMSCs from mice fed an HFD. Conversely, increased SOD2 levels were observed in BMSCs treated with 1,25(OH) 2 D, accompanied by a reduction in BMSC senescence.…”

Section: Discussionsupporting

confidence: 87%

Multiomics profiling reveals VDR as a central regulator of mesenchymal stem cell senescence with a known association with osteoporosis after high-fat diet exposure

Chen,

Kuang,

Cen

et al. 2024

Int J Oral Sci

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The consumption of a high-fat diet (HFD) has been linked to osteoporosis and an increased risk of fragility fractures. However, the specific mechanisms of HFD-induced osteoporosis are not fully understood. Our study shows that exposure to an HFD induces premature senescence in bone marrow mesenchymal stem cells (BMSCs), diminishing their proliferation and osteogenic capability, and thereby contributes to osteoporosis. Transcriptomic and chromatin accessibility analyses revealed the decreased chromatin accessibility of vitamin D receptor (VDR)-binding sequences and decreased VDR signaling in BMSCs from HFD-fed mice, suggesting that VDR is a key regulator of BMSC senescence. Notably, the administration of a VDR activator to HFD-fed mice rescued BMSC senescence and significantly improved osteogenesis, bone mass, and other bone parameters. Mechanistically, VDR activation reduced BMSC senescence by decreasing intracellular reactive oxygen species (ROS) levels and preserving mitochondrial function. Our findings not only elucidate the mechanisms by which an HFD induces BMSC senescence and associated osteoporosis but also offer new insights into treating HFD-induced osteoporosis by targeting the VDR-superoxide dismutase 2 (SOD2)-ROS axis.

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Section: Discussionsupporting

confidence: 87%

Multiomics profiling reveals VDR as a central regulator of mesenchymal stem cell senescence with a known association with osteoporosis after high-fat diet exposure

Chen,

Kuang,

Cen

et al. 2024

Int J Oral Sci

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“…These results point to the association between NLI and long-term heart pathology because the decreased activity of the gene modules related to glutathione metabolism, metabolism of lipids, and aerobic respiration are well-known features of cardiovascular diseases and hypertension [ 74 , 98 , 114 ]. Moreover, it was indicated that the decreased activity of antioxidant system affects the cell differentiation state and can change the cell fate [ 115 , 116 , 117 ]. In accordance, glutathione deficiency was associated with structural cardiac abnormalities in patients with heart diseases and patients with still undetected cardiovascular pathologies, thus suggesting that a blood test including glutathione measuring can be used as a biomarker for asymptomatic cardiovascular disease detection [ 118 , 119 ].…”

Section: Resultsmentioning

confidence: 99%

Long-Term Transcriptomic Changes and Cardiomyocyte Hyperpolyploidy after Lactose Intolerance in Neonatal Rats

Anatskaya

Runov

Ponomartsev

et al. 2023

IJMS

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Many cardiovascular diseases originate from growth retardation, inflammation, and malnutrition during early postnatal development. The nature of this phenomenon is not completely understood. Here we aimed to verify the hypothesis that systemic inflammation triggered by neonatal lactose intolerance (NLI) may exert long-term pathologic effects on cardiac developmental programs and cardiomyocyte transcriptome regulation. Using the rat model of NLI triggered by lactase overloading with lactose and the methods of cytophotometry, image analysis, and mRNA-seq, we evaluated cardiomyocyte ploidy, signs of DNA damage, and NLI-associated long-term transcriptomic changes of genes and gene modules that differed qualitatively (i.e., were switched on or switched off) in the experiment vs. the control. Our data indicated that NLI triggers the long-term animal growth retardation, cardiomyocyte hyperpolyploidy, and extensive transcriptomic rearrangements. Many of these rearrangements are known as manifestations of heart pathologies, including DNA and telomere instability, inflammation, fibrosis, and reactivation of fetal gene program. Moreover, bioinformatic analysis identified possible causes of these pathologic traits, including the impaired signaling via thyroid hormone, calcium, and glutathione. We also found transcriptomic manifestations of increased cardiomyocyte polyploidy, such as the induction of gene modules related to open chromatin, e.g., “negative regulation of chromosome organization”, “transcription” and “ribosome biogenesis”. These findings suggest that ploidy-related epigenetic alterations acquired in the neonatal period permanently rewire gene regulatory networks and alter cardiomyocyte transcriptome. Here we provided first evidence indicating that NLI can be an important trigger of developmental programming of adult cardiovascular disease. The obtained results can help to develop preventive strategies for reducing the NLI-associated adverse effects of inflammation on the developing cardiovascular system.

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“…However, the iPSCs reprogramming protocol, through viral transduction, is associated with high ROS generation, leading to oxidative damage, impaired cell survival, and increased genetic aberrations. Administration of AOX, such as NAC or vitamin C, improves reprogramming efficiency and reduces genetic abnormalities (Ji et al, 2014), thus validating the paradigm that also during the cell reprogramming, balanced levels of oxidative phosphorylation must be maintained on the route to pluripotency (Skvortsova et al, 2022). Telomere elongation is an iPSCs hallmark, thus the role of SIRTs in pluripotency maintenance has been extensively investigated.…”

Section: Sirts In Cellular Reprogrammingmentioning

confidence: 94%

Sirtuins and redox signaling interplay in neurogenesis, neurodegenerative diseases, and neural cell reprogramming

Mormone

Iorio²,

Abate

et al. 2023

Front. Neurosci.

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Since the discovery of Neural Stem Cells (NSCs) there are still mechanism to be clarified, such as the role of mitochondrial metabolism in the regulation of endogenous adult neurogenesis and its implication in neurodegeneration. Although stem cells require glycolysis to maintain their stemness, they can perform oxidative phosphorylation and it is becoming more and more evident that mitochondria are central players, not only for ATP production but also for neuronal differentiation’s steps regulation, through their ability to handle cellular redox state, intracellular signaling, epigenetic state of the cell, as well as the gut microbiota-brain axis, upon dietary influences. In this scenario, the 8-oxoguanine DNA glycosylase (OGG1) repair system would link mitochondrial DNA integrity to the modulation of neural differentiation. On the other side, there is an increasing interest in NSCs generation, from induced pluripotent stem cells, as a clinical model for neurodegenerative diseases (NDs), although this methodology still presents several drawbacks, mainly related to the reprogramming process. Indeed, high levels of reactive oxygen species (ROS), associated with telomere shortening, genomic instability, and defective mitochondrial dynamics, lead to pluripotency limitation and reprogramming efficiency’s reduction. Moreover, while a physiological or moderate ROS increase serves as a signaling mechanism, to activate differentiation and suppress self-renewal, excessive oxidative stress is a common feature of NDs and aging. This ROS-dependent regulatory effect might be modulated by newly identified ROS suppressors, including the NAD+-dependent deacetylase enzymes family called Sirtuins (SIRTs). Recently, the importance of subcellular localization of NAD synthesis has been coupled to different roles for NAD in chromatin stability, DNA repair, circadian rhythms, and longevity. SIRTs have been described as involved in the control of both telomere’s chromatin state and expression of nuclear gene involved in the regulation of mitochondrial gene expression, as well as in several NDs and aging. SIRTs are ubiquitously expressed in the mammalian brain, where they play important roles. In this review we summarize the current knowledge on how SIRTs-dependent modulation of mitochondrial metabolism could impact on neurogenesis and neurodegeneration, focusing mainly on ROS function and their role in SIRTs-mediated cell reprogramming and telomere protection.

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Dual Mode of Mitochondrial ROS Action during Reprogramming to Pluripotency

Cited by 8 publications

References 55 publications

Multiomics profiling reveals VDR as a central regulator of mesenchymal stem cell senescence with a known association with osteoporosis after high-fat diet exposure

Multiomics profiling reveals VDR as a central regulator of mesenchymal stem cell senescence with a known association with osteoporosis after high-fat diet exposure

Long-Term Transcriptomic Changes and Cardiomyocyte Hyperpolyploidy after Lactose Intolerance in Neonatal Rats

Sirtuins and redox signaling interplay in neurogenesis, neurodegenerative diseases, and neural cell reprogramming

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