Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-α prolyl hydroxylase

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.

Succinate: a metabolic signal in inflammation

“…Importantly, mutations in the gene encoding succinate dehydrogenase (SDH), the enzyme responsible for the conversion of succinate to fumarate, were implicated in several cancers, and SDH is now regarded as a tumor suppressor [42]. SDH mutations result in the accumulation of succinate and subsequent HIF-1a stabilization [43], thereby providing a growth advantage for tumors. HIF-1 is a transcriptional regulator in the switch to glycolysis [22] and has been shown to be an important target for succinate.…”

Understanding complexity in the HIF signaling pathway using systems biology and mathematical modeling

“…Since HIF-regulating prolyl-4-hydroxylases utilise -ketoglutarate as a co-substrate and produce succinate during their catalytic activity, it is not surprising that the accumulation of succinate blocks these hydroxylases [27]. Indeed, loss-of-function mutations in succinate dehydrogenase were found to be inhibitory towards PHDs leading to the stabilisation of HIF- subunits and succinate was identified as the mediator of this effect [28,29]. Thus, PHDs can also integrate metabolism-dependent stimuli in the regulation of HIF- which, in return, induces a panel of adaptive genes forming a classical feedforward loop.…”

Mitochondria and cancer: is there a morphological connection?

“…The first hypothesis postulates that SDH and FH deficiencies increase the production of ROS (Messner and Imlay, 2002;Yankovskaya et al, 2003). An alternative model proposes that succinate, which accumulates due to TCA cycle impairment, acts as a signalling molecule and triggers the activation of hypoxia inducible factor 1a (HIF1a) (Selak et al, 2005). Hypoxia inducible factor 1a promotes adaptation of cells to low-oxygen consumption and activates the transcription of glycolytic genes (Firth et al, 1995;Semenza et al, 1996), stimulating aerobic glycolysis.…”