Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase.
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.
Selak
Mary A
MA
Apoptosis and Tumour Physiology Laboratory, Beatson Institute for Cancer Research, Cancer Research UK Beatson Laboratories, Switchback Road, Glasgow G61 1BD, United Kingdom.
Armour
Sean M
SM
MacKenzie
Elaine D
ED
Boulahbel
Houda
H
Watson
David G
DG
Mansfield
Kyle D
KD
Pan
Yi
Y
Simon
M Celeste
MC
Thompson
Craig B
CB
Gottlieb
Eyal
E
D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D002952:Citric Acid Cycle / Q000502:physiology*; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008928:Mitochondria / Q000378:metabolism; D009857:Oncogenes; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019802:Succinic Acid / Q000378:metabolism*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D019802:Succinic Acid; D011393:Procollagen-Proline Dioxygenase; D013385:Succinate Dehydrogenase; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human