Mitochondrial Complex III ROS Regulate Adipocyte Differentiation

Tormos, Kathryn V.; Ansó, Elena; Hamanaka, Robert B.; Eisenbart, James; Joseph, Joy; Kalyanaraman, Balaraman; Chandel, Navdeep S.

doi:10.1016/j.cmet.2011.08.007

Cited by 564 publications

(498 citation statements)

References 37 publications

Supporting

Mentioning

468

Contrasting

Unclassified

Order By: Relevance

“…20 The signaling mechanisms responsible for initiating or enhancing adipogenic differentiation in MSCs appear to involve the generation of mitochondrial ROS released by the ETC. 21 Suppression of mitochondrial biogenesis by knockdown of mitochondrial transcription factor A (TFAM), which binds mitochondrial DNA and is essential for the transcription of ETC components encoded by the mitochondrial DNA, as well as chemical inhibition of mitochondrial respiration or hypoxic suppression of mitochondrial respiration were all able to mitigate the differentiation of MSCs into adipocytes. 20 Exposure of adult human MSCs to hypoxia or to a prolyl hydroxylase inhibitor, which mimics hypoxia by activating hypoxia-inducible factor signaling, activates the embryonic transcription factors Oct-4 and Nanog, which are normally not expressed in adult stem cells (Fig.…”

Section: Mitochondrial Function In Adult Stem Cellsmentioning

confidence: 99%

Bioenergetic Shifts during Transitions between Stem Cell States (2013 Grover Conference Series)

et al. 2014

View full text Add to dashboard Cite

Two defining characteristics of stem cells are their multilineage differentiation potential (multipotency or pluripotency) and their capacity for self-renewal. Growth factors are well-established regulators of stem cell differentiation and self renewal, but less is known about the influence of the metabolic state on stem cell function. Recent studies investigating cellular metabolism during the differentiation of adult stem cells, human embryonic stem cells (ESCs), and induced pluripotent stem cells have demonstrated that activation of specific metabolic pathways depends on the type of stem cells as well as the lineage cells are differentiating into and that these metabolic pathways can influence the differentiation process. However, some common patterns have emerged, suggesting that undifferentiated stem cells primarily rely on glycolysis to meet energy demands. Our own data indicate that undifferentiated ESCs not only exhibit a low mitochondrial membrane potential but also express high levels of the mitochondrial uncoupling protein 2 and of glutamine metabolism regulators when compared with differentiated cells. More importantly, interventions that target stem cell metabolism are able to either prevent or enhance differentiation. These findings suggest that the metabolic state of stem cells is not just a marker of their differentiation status but also plays an active role in regulating stem cell function. Regulatory metabolic pathways in stem cells may thus serve as important checkpoints that can be modulated to direct the regenerative capacity of stem cells.

show abstract

Section: Mitochondrial Function In Adult Stem Cellsmentioning

confidence: 99%

Bioenergetic Shifts during Transitions between Stem Cell States (2013 Grover Conference Series)

et al. 2014

View full text Add to dashboard Cite

show abstract

“…At the earliest stages of life glycolysis is preferred, as seen in the ESC-to-EpiSC transition (Zhou et al, 2012) and in the switch from oxidative phosphorylation to glycolysis that accompanies the conversion of differentiated cells into iPSCs (Folmes et al, 2011;. Metabolic processes have also recently been coupled to other developmental transitions, including macrophage activation (Tannahill et al, 2013), differentiation of mesenchymal and hematopoietic stem cells, and in the transition of satellite stem cells in muscle (Bracha et al, 2010;Chen et al, 2008;Qian et al, 2016;Takubo et al, 2013;Tormos et al, 2011;reviewed by Shyh-Chang et al, 2013). These studies highlight that metabolic processes are potentially driving regulators of development.…”

Section: Introductionmentioning

confidence: 99%

A YY1-dependent increase in aerobic metabolism is indispensable for intestinal organogenesis

et al. 2016

View full text Add to dashboard Cite

During late gestation, villi extend into the intestinal lumen to dramatically increase the surface area of the intestinal epithelium, preparing the gut for the neonatal diet. Incomplete development of the intestine is the most common gastrointestinal complication in neonates, but the causes are unclear. We provide evidence in mice that Yin Yang 1 (Yy1) is crucial for intestinal villus development. YY1 loss in the developing endoderm had no apparent consequences until late gestation, after which the intestine differentiated poorly and exhibited severely stunted villi. Transcriptome analysis revealed that YY1 is required for mitochondrial gene expression, and ultrastructural analysis confirmed compromised mitochondrial integrity in the mutant intestine. We found increased oxidative phosphorylation gene expression at the onset of villus elongation, suggesting that aerobic respiration might function as a regulator of villus growth. Mitochondrial inhibitors blocked villus growth in a fashion similar to Yy1 loss, thus further linking oxidative phosphorylation with late-gestation intestinal development. Interestingly, we find that necrotizing enterocolitis patients also exhibit decreased expression of oxidative phosphorylation genes. Our study highlights the still unappreciated role of metabolic regulation during organogenesis, and suggests that it might contribute to neonatal gastrointestinal disorders.

show abstract

“…In fact, similar to lung CSCs that present decreased ROS and ATP in comparison with their non-stem counterpart, 22 a role in stemness and differentiation was attributed to ROS. 31 Likewise, it was previously showed that ROS produced by complex III stimulates differentiation of mesenchymal stromal cells, 36 and that human ESCs and induced pluripotent SCs have low levels of ROS, which increase during differentiation. 31 Curiously, mRNA levels of…”

mentioning

confidence: 99%

Mitochondrial metabolism directs stemness and differentiation in P19 embryonal carcinoma stem cells

et al. 2014

View full text Add to dashboard Cite

The relationship between mitochondrial metabolism and cell viability and differentiation in stem cells (SCs) remains poorly understood. In the present study, we compared mitochondrial physiology and metabolism between P19SCs before/after differentiation and present a unique fingerprint of the association between mitochondrial activity, cell differentiation and stemness. In comparison with their differentiated counterparts, pluripotency of P19SCs was correlated with a strong glycolytic profile and decreased mitochondrial biogenesis and complexity: round, low-polarized and inactive mitochondria with a closed permeability transition pore. This decreased mitochondrial capacity increased their resistance against dichloroacetate. Thus, stimulation of mitochondrial function by growing P19SCs in glutamine/pyruvate-containing medium reduced their glycolytic phenotype, induced loss of pluripotent potential, compromised differentiation and became P19SCs sensitive to dichloroacetate. Because of the central role of this type of SCs in teratocarcinoma development, our findings highlight the importance of mitochondrial metabolism in stemness, proliferation, differentiation and chemoresistance. In addition, the present work suggests the regulation of mitochondrial metabolism as a tool for inducing cell differentiation in stem line therapies. Embryonal carcinoma cells, including the P19 cell line, are pluripotent cancer stem cells (CSCs) derived from pluripotent germ cell tumors called teratocarcinomas. These have been described as the malignant counterparts of embryonic stem cells (ESCs) and are considered a good model to study stem cell (SC) differentiation. The P19 cell line can be maintained as undifferentiated cells (P19SCs) or differentiated (P19dCs) to any cell type of the three germ layers. Similar to ESCs, P19 cells differentiate with retinoic acid (RA) in a dose-dependent manner and depending on growth conditions. 1 Although differentiation generally yields a mixed population of differentiated cells, P19 cells grown in monolayer and treated with 1 mM RA primarily differentiate in endoderm or mesoderm, while retaining their immortality. 2,3Although some therapeutic approaches for regenerative medicine and to targeting CSCs are based on differentiation 4 and mitochondrial-targeted therapies, 5,6 very little is known about the role of mitochondrial metabolism in SC maintenance and differentiation.7 Several mitochondrial characteristics that distinguish transformed cells from healthy cells have been described, 8 including increased mitochondrial transmembrane electric potential (Dcm), which may result from decreased mitochondrial ATP production under normoxia. Similarly, normal SCs primarily rely on glycolysis for energy supply, although the exact mechanism how this occurs in the presence of oxygen and the relationship between SC metabolism and cell fate control is not yet completely understood. 10Given the mitochondrial involvement in stemness and differentiation, 11 one can ask whether manipulation of mitochondrial physi...

show abstract

Mitochondrial Complex III ROS Regulate Adipocyte Differentiation

Cited by 564 publications

References 37 publications

Bioenergetic Shifts during Transitions between Stem Cell States (2013 Grover Conference Series)

Bioenergetic Shifts during Transitions between Stem Cell States (2013 Grover Conference Series)

A YY1-dependent increase in aerobic metabolism is indispensable for intestinal organogenesis

Mitochondrial metabolism directs stemness and differentiation in P19 embryonal carcinoma stem cells

Contact Info

Product

Resources

About