Mitochondrial retrograde signaling induces epithelial–mesenchymal transition and generates breast cancer stem cells

Guha, Manti; Srinivasan, Satish; Ruthel, Gordon; Kashina, Anna; Carstens, Russ P.; Mendoza, Arnulfo; Khanna, Chand; Winkle, Thomas Van; Avadhani, Narayan G.

doi:10.1038/onc.2013.467

Cited by 119 publications

(122 citation statements)

References 55 publications

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“…Consistent with that, ATP modulation by retrograde signaling experiments resulted in a large effect on translation apparatus gene expression (Chae et al 2013;Guha et al 2014). However, retrograde signaling experiments, although informative, do not reflect the physiological role of the natural variation of mitochondrial content on gene expression regulation.…”

Section: Discussionsupporting

confidence: 59%

“…However, retrograde signaling experiments, although informative, do not reflect the physiological role of the natural variation of mitochondrial content on gene expression regulation. Mitochondrial DNA depletion causes, among others, increased reactive oxygen species (ROS) production and perturbation of cytosolic Ca 2+ , which both signal to the cell nucleus (Chae et al 2013;Guha et al 2014), affecting processes like alternative splicing (Vivarelli et al 2013). We have analyzed the contribution of ROS to RNA Pol II transcription and ATP production, and we have seen that both processes are very sensitive to ROS (Supplemental Fig.…”

Section: Discussionmentioning

confidence: 99%

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Global variability in gene expression and alternative splicing is modulated by mitochondrial content

et al. 2015

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Noise in gene expression is a main determinant of phenotypic variability. Increasing experimental evidence suggests that genome-wide cellular constraints largely contribute to the heterogeneity observed in gene products. It is still unclear, however, which global factors affect gene expression noise and to what extent. Since eukaryotic gene expression is an energy demanding process, differences in the energy budget of each cell could determine gene expression differences. Here, we quantify the contribution of mitochondrial variability (a natural source of ATP variation) to global variability in gene expression. We find that changes in mitochondrial content can account for ∼50% of the variability observed in protein levels. This is the combined result of the effect of mitochondria dosage on transcription and translation apparatus content and activities. Moreover, we find that mitochondrial levels have a large impact on alternative splicing, thus modulating both the abundance and type of mRNAs. A simple mathematical model in which mitochondrial content simultaneously affects transcription rate and splicing site choice can explain the alternative splicing data. The results of this study show that mitochondrial content (and/or probably function) influences mRNA abundance, translation, and alternative splicing, which ultimately affects cellular phenotype.[Supplemental material is available for this article.] Cellular heterogeneity can result from noise generated during gene expression and plays an essential role in fundamental processes such as development, cell differentiation, and cancer (Raj and van Oudenaarden 2008;Eldar and Elowitz 2010;Balázsi et al. 2011). Gene expression noise may originate from stochasticity in the biochemical reactions at an individual gene (intrinsic noise) or from fluctuations in cellular components inducing a global effect (extrinsic noise) (Elowitz et al. 2002;Maheshri and O'Shea 2007). Extrinsic noise is often a dominant source of variation both in prokaryotes (Taniguchi et al. 2010) and eukaryotes (Raser and O'Shea 2004;Newman et al. 2006). Despite this, the origins of extrinsic fluctuations are mostly unknown, although random protein partitioning from cell growth and division (Rosenfeld et al. 2005;Volfson et al. 2006), upstream transcription factors (Volfson et al. 2006), or cell cycle stage (Zopf et al. 2013) have been shown to contribute to variability in protein levels. A common constraint across eukaryotic gene expression is its high energy cost (with ∼75% of the ATP cellular energy budget invested into mRNA and protein polymerization) (Forster et al. 2003;Wagner 2005;Lane and Martin 2010), where every step, from chromatin remodeling to transcription elongation, assembly of splicing factors, and translation, depends on energy (Fig. 1A). Since most of the energy required in normal cells is supplied by mitochondrial oxidative phosphorylation (Vander Heiden et al. 2009), variability in the number and/or functionality of mitochondria is a natural source of variability in ATP content...

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Section: Discussionsupporting

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Global variability in gene expression and alternative splicing is modulated by mitochondrial content

et al. 2015

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“…9 Moreover, metabolically distinct subsets of CSCs have been found in relation to an epithelial-mesenchymal transition (EMT) phenotype. 10 However, this matter is further complicated by the fact that functionally distinct CSCs subpopulations may interact with the tumor microenvironment through secreted and excreted metabolic products. This could constitute yet another level of complexity in tumor metabolism in which the CSC niche may substantially contribute to the regional/clonal metabolic phenotype.…”

mentioning

confidence: 99%

More challenges ahead—metabolic heterogeneity of pancreatic cancer stem cells

Heeschen

Sancho

2016

Molecular & Cellular Oncology

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“…In cancer cell models, mitochondrial dysfunction promotes cell proliferation, increased tumourigenicity, invasiveness, and the epithelial-to-mesenchymal transition via retrograde signaling (7,58). In these models, inhibition of retrograde signaling prevents these tumourigenic phenotypes.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial retrograde signaling regulates neuronal function

Cagin

Duncan

Gatt

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Mitochondria are key regulators of cellular homeostasis, and mitochondrial dysfunction is strongly linked to neurodegenerative diseases, including Alzheimer’s and Parkinson’s. Mitochondria communicate their bioenergetic status to the cell via mitochondrial retrograde signaling. To investigate the role of mitochondrial retrograde signaling in neurons, we induced mitochondrial dysfunction in the Drosophila nervous system. Neuronal mitochondrial dysfunction causes reduced viability, defects in neuronal function, decreased redox potential, and reduced numbers of presynaptic mitochondria and active zones. We find that neuronal mitochondrial dysfunction stimulates a retrograde signaling response that controls the expression of several hundred nuclear genes. We show that the Drosophila hypoxia inducible factor alpha (HIFα) ortholog Similar (Sima) regulates the expression of several of these retrograde genes, suggesting that Sima mediates mitochondrial retrograde signaling. Remarkably, knockdown of Sima restores neuronal function without affecting the primary mitochondrial defect, demonstrating that mitochondrial retrograde signaling is partly responsible for neuronal dysfunction. Sima knockdown also restores function in a Drosophila model of the mitochondrial disease Leigh syndrome and in a Drosophila model of familial Parkinson’s disease. Thus, mitochondrial retrograde signaling regulates neuronal activity and can be manipulated to enhance neuronal function, despite mitochondrial impairment.

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Mitochondrial retrograde signaling induces epithelial–mesenchymal transition and generates breast cancer stem cells

Cited by 119 publications

References 55 publications

Global variability in gene expression and alternative splicing is modulated by mitochondrial content

Global variability in gene expression and alternative splicing is modulated by mitochondrial content

More challenges ahead—metabolic heterogeneity of pancreatic cancer stem cells

Mitochondrial retrograde signaling regulates neuronal function

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