Elevated CO2 Levels Cause Mitochondrial Dysfunction and Impair Cell Proliferation

Vohwinkel, Christine U.; Lecuona, Emilia; Sun, Haiying; Sommer, Natascha; Vadász, István; Chandel, Navdeep S.; Sznajder, Jacob I.

doi:10.1074/jbc.m111.290056

Cited by 155 publications

(168 citation statements)

References 46 publications

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“…Previously, Vohwinkel et al (2011) reported that high CO 2 levels induced miR-183 and observed a decrease in IDH2 mRNA and protein, but the miR-183-IDH2 interaction was not conclusively confirmed. Although the exact role of IDH1/2 in tumorigenesis is unclear, these enzymes convert isocitrate to a-ketoglutarate, which is a citric acid cycle metabolite and a cofactor for more than 60 enzymes, including EGL-Nine (EGLN) homologs (Raimundo et al 2011, Borodovsky et al 2012.…”

Section: Discussionmentioning

confidence: 85%

Integrative analysis of miRNA and mRNA expression profiles in pheochromocytoma and paraganglioma identifies genotype-specific markers and potentially regulated pathways

Cubas¹,

Leandro‐García²,

Schiavi³

et al. 2013

Endocrine-Related Cancer

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Pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare neuroendocrine neoplasias of neural crest origin that can be part of several inherited syndromes. Although their mRNA profiles are known to depend on genetic background, a number of questions related to tumor biology and clinical behavior remain unanswered. As microRNAs (miRNAs) are key players in the modulation of gene expression, their comprehensive analysis could resolve some of these issues. Through characterization of miRNA profiles in 69 frozen tumors with germline mutations in the genes SDHD, SDHB, VHL, RET, NF1, TMEM127, and MAX, we identified miRNA signatures specific to, as well as common among, the genetic groups of PCCs/PGLs. miRNA expression profiles were validated in an independent series of 30 composed of VHL-, SDHB-, SDHD-, and RET-related formalin-fixed paraffin-embedded PCC/PGL samples using quantitative real-time PCR. Upregulation of miR-210 in VHL-and SDHB-related PCCs/PGLs was verified, while miR-137 and miR-382 were confirmed as generally upregulated in PCCs/PGLs (except in MAX-related tumors). Also, we confirmed overexpression of miR-133b as VHL-specific miRNAs, miR-488 and miR-885-5p as RET-specific miRNAs, and miR-183 and miR-96 as SDHB-specific miRNAs. To determine the potential roles miRNAs play in PCC/PGL pathogenesis, we performed bioinformatic integration and pathway analysis using matched mRNA profiling data that indicated a common enrichment Finally, global proteomic analysis in SDHB and MAX tumors allowed us to determine that miRNA regulation occurs primarily through mRNA degradation in PCCs/PGLs, which partially confirmed our miRNA-mRNA integration results.

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Section: Discussionmentioning

confidence: 85%

Integrative analysis of miRNA and mRNA expression profiles in pheochromocytoma and paraganglioma identifies genotype-specific markers and potentially regulated pathways

Cubas¹,

Leandro‐García²,

Schiavi³

et al. 2013

Endocrine-Related Cancer

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“…Previous evidence from lung alveolar epithelialcellssuggeststhatCO 2 -mediatedAMPK␣1phosphor-ylation occurs through Ca 2ϩ /calmodulin-dependent kinase kinase ␤ (CaMKK-␤) (27), making this pathway a possible activator of AMPK in the present model. Alternatively, given that CO 2 exposure was found to cause mitochondrial dysfunction, decreased O 2 consumption, and ATP production in fibroblasts and alveolar epithelial cells (52), AMPK activation could also occur via LKB1. Interestingly, it has been reported that AMPK␣2 activity is more dependent on high AMP levels than the ␣1 isoform (53), making CO 2 -driven mitochondrial dysfunction an interesting potential upstream activator of AMPK, which should be further addressed in future works.…”

Section: Discussionmentioning

confidence: 99%

High CO2 Levels Cause Skeletal Muscle Atrophy via AMP-activated Kinase (AMPK), FoxO3a Protein, and Muscle-specific Ring Finger Protein 1 (MuRF1)

Jaitovich

Angulo

Lecuona

et al. 2015

Journal of Biological Chemistry

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104

134

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Background: CO 2 retention and skeletal muscle atrophy occur in patients with lung diseases and are associated with poor clinical outcomes. Results: Hypercapnia leads to AMPK/FoxO3a/MuRF1-dependent muscle fiber size reduction. Conclusion: Hypercapnia activates a signaling pathway leading to skeletal muscle atrophy. Significance: High CO 2 levels directly activate a proteolytic program of skeletal muscle atrophy which is of relevance to patients with lung diseases.

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“…The first definite evidence that miR-103 and miR-107 participate in cellular acetyl-CoA and lipid synthesis through upregulating pantothenate kinase enzyme (Wilfred et al, 2007). mRNA and protein expression levels of IDH2 are downregulated by miR-183 in glioma cells (Vohwinkel et al, 2011;Tanaka et al, 2013). SDH was validated as a bona fide miR-210 target.…”

Section: Tca Cyclementioning

confidence: 99%

Role of MicroRNAs in the Warburg Effect and Mitochondrial Metabolism in Cancer

Jin

Chen²

2014

Asian Pacific Journal of Cancer Prevention

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Metabolism lies at the heart of cell biology. The metabolism of cancer cells is significantly different from that of their normal counterparts during tumorigenesis and progression. Elevated glucose metabolism is one of the hallmarks of cancer cells, even under aerobic conditions. The Warburg effect not only allows cancer cells to meet their high energy demands and supply biological materials for anabolic processes including nucleotide and lipid synthesis, but it also minimizes reactive oxygen species production in mitochondria, thereby providing a growth advantage for tumors. Indeed, the mitochondria also play a more essential role in tumor development. As information about the numorous microRNAs has emerged, the importance of metabolic phenotypes mediated by microRNAs in cancer is being increasingly emphasized. However, the consequences of dysregulation of Warburg effect and mitochondrial metabolism modulated by microRNAs in tumor initiation and progression are still largely unclear.

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Elevated CO2 Levels Cause Mitochondrial Dysfunction and Impair Cell Proliferation

Cited by 155 publications

References 46 publications

Integrative analysis of miRNA and mRNA expression profiles in pheochromocytoma and paraganglioma identifies genotype-specific markers and potentially regulated pathways

Integrative analysis of miRNA and mRNA expression profiles in pheochromocytoma and paraganglioma identifies genotype-specific markers and potentially regulated pathways

High CO2 Levels Cause Skeletal Muscle Atrophy via AMP-activated Kinase (AMPK), FoxO3a Protein, and Muscle-specific Ring Finger Protein 1 (MuRF1)

Role of MicroRNAs in the Warburg Effect and Mitochondrial Metabolism in Cancer

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