Abstract
Several mitochondrial proteins are tumor suppressors. These include succinate dehydrogenase (SDH) and fumarate hydratase, both enzymes of the tricarboxylic acid (TCA) cycle. However, to date, the mechanisms by which defects in the TCA cycle contribute to tumor formation have not been elucidated. Here we describe a mitochondrion-to-cytosol signaling pathway that links mitochondrial dysfunction to oncogenic events: succinate, which accumulates as a result of SDH inhibition, inhibits HIF-alpha prolyl hydroxylases in the cytosol, leading to stabilization and activation of HIF-1alpha. These results suggest a mechanistic link between SDH mutations and HIF-1alpha induction, providing an explanation for the highly vascular tumors that develop in the absence of VHL mutations.
MeSH terms
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Animals
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Cell Line
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Cell Transformation, Neoplastic
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Citric Acid Cycle / physiology*
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Enzyme Activation
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Gene Expression Regulation, Enzymologic
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit
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Mitochondria / metabolism
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Oncogenes*
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Procollagen-Proline Dioxygenase / antagonists & inhibitors
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Procollagen-Proline Dioxygenase / genetics
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Procollagen-Proline Dioxygenase / metabolism*
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Reactive Oxygen Species / metabolism
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Signal Transduction / physiology
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Succinate Dehydrogenase / antagonists & inhibitors
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Succinate Dehydrogenase / genetics
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Succinate Dehydrogenase / metabolism
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Succinic Acid / metabolism*
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Transcription Factors / antagonists & inhibitors
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism
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Von Hippel-Lindau Tumor Suppressor Protein
Substances
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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RNA, Small Interfering
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Reactive Oxygen Species
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Transcription Factors
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Tumor Suppressor Proteins
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Succinic Acid
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Procollagen-Proline Dioxygenase
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Succinate Dehydrogenase
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Ubiquitin-Protein Ligases
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Von Hippel-Lindau Tumor Suppressor Protein
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VHL protein, human