Activation of a Novel Calcineurin-mediated Insulin-like Growth Factor-1 Receptor Pathway, Altered Metabolism, and Tumor Cell Invasion in Cells Subjected to Mitochondrial Respiratory Stress

Guha, Manti; Srinivasan, Satish; Biswas, Gopa; Avadhani, Narayan G.

doi:10.1074/jbc.m611693200

Cited by 52 publications

(98 citation statements)

References 54 publications

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“…1D to G). These results are concordant with the low activity of glycolytic enzymes of A549 cells compared with C2C12 muscle-derived cell line reported by Guha,30 and the small glycolytic contribution (»5%) to the total ATP produced by A549 cells. 31 The state 3 and 4 mitochondrial membrane potential and their ratio paralleled the mitochondrial ATP synthesis activity (relative to CS, Fig.…”

Section: Rdmyo Cells Have a Higher Bioenergetic Profile Than A549b2supporting

confidence: 79%

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Mitochondrial quality control: Cell-type-dependent responses to pathological mutant mitochondrial DNA

et al. 2016

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Pathological mutations in the mitochondrial DNA (mtDNA) produce a diverse range of tissue-specific diseases and the proportion of mutant mitochondrial DNA can increase or decrease with time via segregation, dependent on the cell or tissue type. Previously we found that adenocarcinoma (A549.B2) cells favored wild-type (WT) mtDNA, whereas rhabdomyosarcoma (RD.Myo) cells favored mutant (m3243G) mtDNA. Mitochondrial quality control (mtQC) can purge the cells of dysfunctional mitochondria via mitochondrial dynamics and mitophagy and appears to offer the perfect solution to the human diseases caused by mutant mtDNA. In A549.B2 and RD.Myo cybrids, with various mutant mtDNA levels, mtQC was explored together with macroautophagy/autophagy and bioenergetic profile. The 2 types of tumor-derived cell lines differed in bioenergetic profile and mitophagy, but not in autophagy. A549.B2 cybrids displayed upregulation of mitophagy, increased mtDNA removal, mitochondrial fragmentation and mitochondrial depolarization on incubation with oligomycin, parameters that correlated with mutant load. Conversely, heteroplasmic RD.Myo lines had lower mitophagic markers that negatively correlated with mutant load, combined with a fully polarized and highly fused mitochondrial network. These findings indicate that pathological mutant mitochondrial DNA can modulate mitochondrial dynamics and mitophagy in a cell-type dependent manner and thereby offer an explanation for the persistence and accumulation of deleterious variants.

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Section: Rdmyo Cells Have a Higher Bioenergetic Profile Than A549b2supporting

confidence: 79%

“…In line with previous in vitro [30][31][32] and in vivo results, 33 A549.B2 cells displayed low glycolytic capacity and reduced mitochondrial mass, on the contrary, RD.Myo cybrids showed high glycolytic and oxidative phosphorylation capacity.…”

Section: Rdmyo Cells Have a Higher Bioenergetic Profile Than A549b2supporting

confidence: 71%

Mitochondrial quality control: Cell-type-dependent responses to pathological mutant mitochondrial DNA

et al. 2016

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“…18 The mechanism for this effect appears to be mediated via elevated cytosolic calcium that activates calcineurin, which in turn leads to diverse downstream nuclear gene reprogramming. 19,20 Moreover, IGF1R links to upregulated glucose transporters in these circumstances, which is also a cardinal finding of SDHB-associated phaeochromocytoma-paragangliomas. 21 We therefore speculate that SDHB deficiency, either due to germline mutation (as in phaeochromocytoma and paraganglioma) or due to some yet-to-be-identified acquired mechanism, may induce IGF1R expression via the same downstream consequences of mitochondrial dysfunction.…”

Section: Discussionmentioning

confidence: 98%

Succinate dehydrogenase-deficient GISTs are characterized by IGF1R overexpression

et al. 2012

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Succinate dehydrogenase-deficient gastrointestinal stromal tumors (GISTs) demonstrate unique pathological and clinical features, including the absence of activating mutations of KIT and PDGFRA, and primary resistance to imatinib. They arise exclusively in the stomach and account for 5-7.5% of all adult stomach GISTs and the great majority of these tumors in childhood. Insulin-like growth factor 1 receptor (IGF1R) overexpression has been associated with wild-type and pediatric GISTs. We propose that IGF1R overexpression is a feature of succinate dehydrogenase-deficient GISTs as a group. We assessed succinate dehydrogenase complex subunit B (SDHB) and IGF1R expression by immunohistochemistry in eight known succinate dehydrogenase-deficient GISTs, three GISTs arising in the setting of neurofibromatosis type 1 syndrome and 40 unselected GISTs. Selected KIT and PDGFRA exons were amplified and sequenced from formalin-fixed paraffin-embedded tumor samples. All eight succinate dehydrogenase-deficient tumors were wild-type for KIT and PDGFRA, succinate dehydrogenase B negative and demonstrated IGF1R overexpression. The three neurofibromatosis-related tumors were succinate dehydrogenase B positive and IGF1R negative. Of the 40 unselected upper GISTs, five were wild-type for KIT and PDGFRA in the selected exons. Two of the wild-type GISTs were succinate dehydrogenase B negative and showed IGF1R overexpression and three were succinate dehydrogenase B positive and IGF1R negative. We conclude that IGF1R overexpression is a feature of succinate dehydrogenase deficient GIST as a group, rather than pediatric or wild-type GIST per se. Therefore, IGF1R inhibition represents a potential rational therapeutic approach in this recently recognized subgroup of GIST.

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“…Concomitant with our findings, previous studies have shown that in yeast, Drosophila, and mammalian-proliferating cells, retrograde signaling activates the expression of hypoxic/glycolytic genes and the insulin-like growth factor-1 receptor pathway to compensate for mitochondrial dysfunction (20,46,49). Rtg1 and Rtg3, the transcription factors that coordinate the mitochondrial retrograde response in yeast, are not conserved in metazoans.…”

Section: Discussionmentioning

confidence: 49%

“…Rtg1 and Rtg3, the transcription factors that coordinate the mitochondrial retrograde response in yeast, are not conserved in metazoans. In mammalian proliferating cellular models, the retrograde response activates the transcription factors nuclear factor of activated T cells (NFAT), CAAT/enhancer binding protein δ (C/EBPδ), cAMPresponsive element binding protein (CREB), and an IκBβ-dependent nuclear factor κB (NFκB) c-Rel/p50 (49)(50)(51). Whether these transcription factors regulate mitochondrial retrograde signaling in the mammalian nervous system is not known.…”

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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Activation of a Novel Calcineurin-mediated Insulin-like Growth Factor-1 Receptor Pathway, Altered Metabolism, and Tumor Cell Invasion in Cells Subjected to Mitochondrial Respiratory Stress

Cited by 52 publications

References 54 publications

Mitochondrial quality control: Cell-type-dependent responses to pathological mutant mitochondrial DNA

Mitochondrial quality control: Cell-type-dependent responses to pathological mutant mitochondrial DNA

Succinate dehydrogenase-deficient GISTs are characterized by IGF1R overexpression

Mitochondrial retrograde signaling regulates neuronal function

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