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

Selak, Mary A.; Armour, Sean M.; MacKenzie, Elaine D.; Boulahbel, Houda; Watson, David G.; Mansfield, Kyle D.; Pan, Yi; Simon, M.Celeste; Thompson, Craig B.; Gottlieb, Eyal

doi:10.1016/j.ccr.2004.11.022

Cited by 2,108Cancer, Hypoxia, and MetabolismEar and Head TumorsFerroptosis and cancer prognosis

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

Open access

Selak, Mary A., Armour, Sean M., MacKenzie, Elaine D., Boulahbel, Houda, Watson, David G., Mansfield, Kyle D., Pan, Yi, Simon, M.Celeste +2 more·2005·Cancer Cell

DOI 10.1016/j.ccr.2004.11.022

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Abstract

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

AI snapshot

Written from the paper’s full text.

TL;DR

In HEK293 cells, knocking down the SDHD subunit of succinate dehydrogenase caused succinate to accumulate and inhibited HIF-α prolyl hydroxylases, stabilizing HIF-1α under normoxic conditions. This provides a mechanism linking TCA cycle dysfunction to vascular tumor phenotypes without VHL mutation.

Key findings

SDHD-targeting siRNA reduced SDH activity and raised cellular succinate from about 121 µM in controls to about 447 µM (Di3) and 441 µM (Di4); no significant change was seen in DHE oxidation or glutathione redox state, arguing against ROS as the mediator.
SDH inhibition induced HIF-1α protein under normoxia, produced about a 3-fold increase in HRE-luciferase reporter activity, induced VEGF mRNA to levels comparable with hypoxia or CoCl₂, and increased BNIP3; HIF-2α induction was less pronounced.
Succinate inhibited PHD activity in vitro in a dose-dependent manner, with an IC50 reported as 0.5 mM, and the membrane-permeable succinate derivative DMS (20 mM, 48 hr) elevated HIF-1α and caused nuclear HIF-1α accumulation under normoxia.
In SDH-inhibited cells, pVHL binding to the ODD domain was reduced, consistent with decreased ODD hydroxylation; the proposed model is that mitochondrial succinate exits to the cytosol, inhibits PHD, stabilizes HIF-1α, and drives angiogenesis, metastasis, and glycolytic gene expression.

Methods

HEK293 cells were transfected with scrambled siRNA or SDHD-targeting siRNA (Di3 or Di4); SDH activity was measured by succinate-DCIP oxidoreductase, succinate by GC-MS with deuterated succinic acid as reference, and ROS/redox state by DHE staining and glutathione assays.
HIF readouts included Western blot for HIF-1α, HIF-2α, and BNIP3, RT-PCR for VEGF, and an HRE-luciferase reporter; PHD activity was assayed in vitro using HA-tagged ODD and cell extracts, and pVHL binding was assessed by immunoprecipitation and far Western blot.
The study is cell-culture based, with no patient tumor samples or in vivo tumor models described.

Limitations

Stated in the paper: DMS uptake, conversion to succinate, and metabolism are unknown; different cell types may have different thresholds and mechanisms of HIF activation; succinate may also modulate FIH; and the ROS findings conflict with C. elegans mev-1 observations, possibly due to species or mutation differences.
Evident from the text: conclusions rely on HEK293 cells and siRNA knockdown rather than SDH-mutant tumors, transfection efficiency was about 50% so populations were mixed, and no in vivo tumor growth or patient tumor validation was performed; elevated succinate in human SDH-mutant tumors is cited as personal communication.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.ccr.2004.11.022

Cites

45 of 45 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

1 of 7 cited sources checked · 1 supported · 0 flagged

Premisecitation
pVHL binding to the ODD domain is dependent on PHD activity.
“Since pVHL binding to the ODD domain is dependent on PHD activity (Kaelin, 2002;Safran and Kaelin, 2003)”
Quote in the paperSubstantial claim1 of 2 sources checked
- cites Kaelin, 2002 source
- cites Safran and Kaelin, 2003 source
Findingnone given
Succinate accumulates as a result of SDH inhibition.
“succinate, which accumulates as a result of SDH inhibition, inhibits HIF-␣ prolyl hydroxylases in the cytosol”
Quote in the paperSubstantial claim
Findingown data
Cells incubated with 20 mM DMS for 48 hours show elevated HIF-1alpha levels under normoxic conditions.
“cells incubated with 20 mM DMS for 48 hr showed elevated levels of HIF-1␣ under normoxic conditions (Figure 5B).”
Quote in the paperSubstantial claim
Findingown data
Reactive oxygen species do not play a role in HIF-1alpha induction after SDH inhibition.
“Reactive oxygen species do not play a role in HIF-1␣ induction after SDH inhibition”
- Also stated in: § Reactive oxygen species do not play a role in HIF-1␣ induction after SDH inhibition · plain
  “there was no detectable difference in DHE oxidation in Di3 and Di4-transfected cells relative to the control (compare Figures 3C and 3D to 3A).”
- Also stated in: § Reactive oxygen species do not play a role in HIF-1␣ induction after SDH inhibition · plain
  “no significant difference was observed in the redox state of SDH-inhibited cells as compared to the control scRNAi-transfected cells (Table 1).”
Quote in the paperSubstantial claim
Findingown data
In Di3-transfected cells, pVHL-associated GFP fluorescence is significantly lower than in scRNAi-transfected cells.
“In Di3-transfected cells, even though the total GFP-ODD level was higher than in scRNAitransfected cells (Figures 6Aiv and 6Av), the levels of pVHLassociated fluorescence were significantly lower (Figure 6C).”
Quote in the paperSubstantial claim

Findingown data
Downregulation of SDH activity results in accumulation of succinate in cells.
“In this paper, we show that downregulation of SDH activity results in the accumulation of succinate in cells”
Quote in the paperSubstantial claim
Findingown data
DMS treatment causes nuclear accumulation of HIF-1alpha.
“a clear accumulation of HIF-1␣ in the nuclei of cells treated with DMS was observed (Figure 5C)”
Quote in the paperSubstantial claim
Findingown data
There is no significant difference in the redox state (GSH/GSSG) of SDH-inhibited cells compared to control scRNAi-transfected cells.
“no significant difference was observed in the redox state of SDH-inhibited cells as compared to the control scRNAi-transfected cells (Table 1).”
Quote in the paperSubstantial claim
Findingown data
There is no detectable difference in DHE oxidation in Di3- and Di4-transfected cells relative to control.
“there was no detectable difference in DHE oxidation in Di3 and Di4-transfected cells relative to the control (compare Figures 3C and 3D to 3A).”
Quote in the paperSubstantial claim
Findingown data
Succinate inhibits HIF-alpha prolyl hydroxylases in the cytosol.
“succinate, which accumulates as a result of SDH inhibition, inhibits HIF-␣ prolyl hydroxylases in the cytosol”
Quote in the paperSubstantial claim
- Rests on an assumption: Succinate moves freely between the mitochondria and the cytosol via the dicarboxylic acid translocator in the mitochondrial inner membrane and the voltage-dependent anion channel (VDAC/porin) in the mitochondrial outer membrane.
- Rests on an assumption: Succinate is the substrate for SDH in mitochondria and a product of PHD in the cytosol.
Findingown data
Inhibition of SDH activity has no effect on ROS production.
“Inhibition of SDH activity has no effect on ROS production”
Quote in the paperSubstantial claim
Findingown data
Inhibition of SDH decreases PHD activity.
“Inhibition of SDH decreases PHD activity”
Quote in the paperSubstantial claim
Findingown data
Inhibition of SDH activity increases HIF activity.
“Inhibition of SDH activity increases HIF-1␣ levels and HIF activity”
Quote in the paperSubstantial claim
Findingown data
HIF-1α is induced in SDH inhibited or hypoxic cells.
“HIF-1␣ and HIF-2␣ induction in SDH inhibited or hypoxic cells”
Quote in the paperSubstantial claim
Findingown data
SDH inhibition leads to increased levels of succinate.
“SDH inhibition leads to increased levels of succinate”
Quote in the paperSubstantial claim
Findingown data
HIF-2α is induced in SDH inhibited or hypoxic cells.
“HIF-1␣ and HIF-2␣ induction in SDH inhibited or hypoxic cells”
Quote in the paperSubstantial claim
Findingown data
Inhibition of SDH activity increases HIF-1α levels.
“Inhibition of SDH activity increases HIF-1␣ levels and HIF activity”
Quote in the paperSubstantial claim
Interpretationreasoning
The mechanism provides an explanation for highly vascular tumors that develop in the absence of VHL mutations.
“These results suggest a mechanistic link between SDH mutations and HIF-1␣ induction, providing an explanation for the highly vascular tumors that develop in the absence of VHL mutations.”
Quote in the paperSubstantial claim
- Rests on an assumption: Succinate moves freely between the mitochondria and the cytosol via the dicarboxylic acid translocator in the mitochondrial inner membrane and the voltage-dependent anion channel (VDAC/porin) in the mitochondrial outer membrane.
Interpretationreasoning
There is a mechanistic link between SDH mutations and HIF-1alpha induction.
“These results suggest a mechanistic link between SDH mutations and HIF-1␣ induction, providing an explanation for the highly vascular tumors that develop in the absence of VHL mutations.”
Quote in the paperSubstantial claim
- Rests on an assumption: Succinate moves freely between the mitochondria and the cytosol via the dicarboxylic acid translocator in the mitochondrial inner membrane and the voltage-dependent anion channel (VDAC/porin) in the mitochondrial outer membrane.

May combine two claims. 3
The quote only partly states this claim. 1
Classified as probably not a substantial claim. 2

May combine two claims.
Findingown data
The IC50 for succinate under these reaction conditions is approximately 0.5 mM, a level attainable in SDH-inhibited cells.
“The IC 50 was ‫5.0ف‬ mM for succinate under these reaction conditions, a level that is attainable in SDH-inhibited cells (Table 1).”
Quote in the paperNot a substantial claim
The quote only partly states this claim.
Interpretationreasoning
Succinate inhibition of PHD leads to stabilization and activation of HIF-1alpha.
“leading to stabilization and activation of HIF-1␣.”
Quote in the paperSubstantial claim
- Rests on an assumption: Succinate moves freely between the mitochondria and the cytosol via the dicarboxylic acid translocator in the mitochondrial inner membrane and the voltage-dependent anion channel (VDAC/porin) in the mitochondrial outer membrane.
Classified as probably not a substantial claim.
Premisecitation
Succinate has been shown to inhibit some alpha-ketoglutarate-dependent oxygenases, including procollagen prolyl hydroxylase and thymine-7-hydroxylase.
“succinate has been shown to inhibit some ␣-ketoglutarate-dependent oxygenases, including procollagen prolyl hydroxylase and thymine-7-hydroxylase (Holme, 1975;Myllyla et al., 1977).”
Quote in the paperSubstantial claim0 of 2 sources checked
- cites Holme, 1975 source
- cites Myllyla et al., 1977 source
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone given
Actin was used as loading control.
“Actin was used as loading control.”
Quote in the paperNot a substantial claim
May combine two claims.
Premisecitation
PHD isozymes split molecular oxygen to hydroxylate their substrates and, in parallel, oxidize and decarboxylate alpha-ketoglutarate to succinate.
“The PHD isozymes belong to the Fe 2ϩ and ␣-ketoglutarate-dependent family of dioxygenases that split molecular oxygen to hydroxylate their substrates and, in parallel, oxidize and decarboxylate ␣-ketoglutarate to succinate (Schofield and Zhang, 1999).”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites Schofield and Zhang, 1999 source
May combine two claims.
Premisecitation
PHDs utilize alpha-ketoglutarate as a cosubstrate and require ferrous iron and ascorbate as cofactors.
“the PHDs utilize ␣-ketoglutarate as a cosubstrate and require ferrous iron (Fe 2ϩ ) and ascorbate as cofactors (Kaelin, 2002;Schofield and Zhang, 1999).”
Quote in the paperSubstantial claim0 of 2 sources checked
- cites Kaelin, 2002 source
- cites Schofield and Zhang, 1999 source

6 of 6

The paper relies on this without support.
Succinate moves freely between the mitochondria and the cytosol via the dicarboxylic acid translocator in the mitochondrial inner membrane and the voltage-dependent anion channel (VDAC/porin) in the mitochondrial outer membrane.
“Succinate moves freely between the mitochondria and the cytosol via the dicarboxylic acid translocator in the mitochondrial inner membrane and the voltage-dependent anion channel (VDAC/porin) in the mitochondrial outer membrane.”
The paper relies on this without support.
Succinate is the substrate for SDH in mitochondria and a product of PHD in the cytosol.
“succinate, the substrate for SDH in mitochondria and a product of PHD in the cytosol.”

2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

In intact cells, lack of enzymatically active CII results in accumulation of its substrate succinate due to poor membrane permeability of this metabolite.
“In intact cells, this introduces an additional level of complexity, because the lack of enzymatically active CII will result in the accumulation of its substrate succinate due to the poor membrane permeability of this metabolite.27”
From Ubiquinone-binding site mutagenesis reveals the role of mitochondrial complex II in cell death initiation (2015) · cites this paper as [27]
The ‘Succinate is accumulated in SDH-inhibited cells’ section reports increased cellular succinate after SDH inhibition. The paper does not establish that poor membrane permeability causes this accumulation. It says succinate moves freely between mitochondria and cytosol, and describes a membrane-permeable succinate derivative, but neither passage demonstrates the claimed causal explanation for intact cells. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Increased succinate and/or fumarate causes stabilization of HIF1a in vivo.
“Our data provide in vivo evidence to support the hypothesis that increased succinate and/or fumarate causes stabilization of HIF1a”
From Accumulation of Krebs cycle intermediates and over-expression of HIF1α in tumours which result from germline FH and SDH mutations (2005) · cites this paper as [27]
Selak et al. tested a model of tumorigenesis in which raised levels of succinate caused increased HIF1a expression in vitro.
“Selak et al. (27) tested a model of tumorigenesis in which raised levels of succinate caused increased HIF1a expression in vitro.”
From Accumulation of Krebs cycle intermediates and over-expression of HIF1α in tumours which result from germline FH and SDH mutations (2005) · cites this paper as [27]
Neither the paper's data nor those of Selak et al. have provided evidence for an alternative model of tumorigenesis in HLRCC or HPGL based on increased levels of reactive oxygen species.
“neither our data nor those of Selak et al. (27) have provided evidence for an alternative model of tumorigenesis in HLRCC or HPGL based on increased levels of ROSs.”
From Accumulation of Krebs cycle intermediates and over-expression of HIF1α in tumours which result from germline FH and SDH mutations (2005) · cites this paper as [27]
Selak et al. showed that the mechanism for these findings may be inhibition by succinate of HIF PHDs, which rely for their activity on conversion of alpha-ketoglutarate to succinate.
“Selak et al. (27) showed that the mechanism for these findings may be inhibition by succinate of HIF PHDs, which rely for their activity on conversion of a-ketoglutarate to succinate.”
From Accumulation of Krebs cycle intermediates and over-expression of HIF1α in tumours which result from germline FH and SDH mutations (2005) · cites this paper as [27]

Succinate and fumarate inhibit prolyl hydroxylase domain-containing enzymes that regulate hypoxia-inducible factor stability, so FH- and SDH-deficient cancers activate the hypoxic gene expression program even under normoxic conditions.
“Additionally, succinate and fumarate inhibit the prolyl hydroxylase domain-containing (PHD) enzymes that regulate stability of hypoxia-inducible factors (HIFs), such that FH and SDH deficient cancers activate the hypoxic gene expression program even under normoxic conditions (Hewitson et al., 2007; Pollard et al., 2005; Selak et al., 2005).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Selak et al., 2005
Metabolite accumulation in dysfunctional mitochondria can inhibit VHL-dependent degradation of HIF-alpha subunits, creating a pseudohypoxic state that mimics VHL loss.
“Metabolite accumulation in the setting of dysfunctional mitochondria can inhibit VHL-dependent degradation of hypoxia-inducible factor-α (HIF-α) subunits, creating a pseudohypoxic state that mimics VHL loss (14).”
From Metabolic reprogramming and cancer progression (2020) · cites this paper as [14]
Succinate supports tumorigenesis through inhibition of PHD, stabilizing HIF-1α and maintaining metabolic reprogramming.
“The other mechanism by which succinate supports tumorigenesis acts through the inhibition of hypoxia-inducible factor prolyl hydroxylase (PHD). PHD activates the pseudohypoxic response by stabilizing HIF-1α, which is a well-known tumorigenesis enhancer”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [127]
TCA cycle dysfunction leads to oncogenesis by regulating signaling pathways and stabilizing HIF1-α.
“TCA cycle dysfunction leads to oncogenesis by regulating signaling pathway and stabilizing HIF1-α (Selak et al., 2005).”
From Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism (2016) · cites this paper as Selak et al., 2005
Dysregulated SDH activity in these mutations increases succinate and mitochondrial reactive oxygen species, activates HIF1α, and induces angiogenesis.
“Dysregulated SDH activity in the setting of these mutations promotes the accumulation of succinate and mitochondrial reactive oxygen species, activating HIF1α and inducing angiogenesis (Selak et al., 2005).”
From SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways (2013) · cites this paper as Selak et al., 2005
H2O2 can participate in the one-electron reaction with transition metal ions (e.g., Fe2+ bound to organic molecules) to generate various intermediate ferryl species, such as Fe(IV) = O•, a powerful oxidizing agent that can lead to lipid oxidation and DNA damage.
“H2O2 also can participate in the one-electron reaction with transition metal ions (e.g., Fe2+ bound to organic molecules) to generate various intermediate ferryl species (274, 275), such as Fe(IV) = O•, a powerful oxidizing agent that can lead to lipid oxidation and DNA damage, as discussed in section VI.”
From Mitochondrial reactive oxygen species production in excitable cells: Modulators of mitochondrial and cell function (2009) · cites this paper as [275]
High levels of succinate resulting from loss of complex II function can block HIF1α degradation through inhibition of prolyl hydroxylases.
“High levels of succinate resulting from loss of complex II function can in turn block HIF1α degradation through inhibition of prolyl hydroxylases.”
From A HIF1α Regulatory Loop Links Hypoxia and Mitochondrial Signals in Pheochromocytomas (2005) · cites this paper as [19]
Disruption of mitochondrial complex II results in increased HIF1α activity and this upregulation is channeled through inhibition of prolyl hydroxylase function.
“Selak et al. showed that disruption of the mitochondrial complex II results in increased HIF1α activity and that this upregulation is channeled through inhibition of prolyl hydroxylase function [19].”
From A HIF1α Regulatory Loop Links Hypoxia and Mitochondrial Signals in Pheochromocytomas (2005) · cites this paper as [19]
Succinate activates HIF-1α in tumours, indicating an important similarity between inflammation and cancer.
“Succinate activates HIF-1α in tumours10,26, indicating an important similarity between inflammation and cancer.”
From Succinate is an inflammatory signal that induces IL-1β through HIF-1α (2013) · cites this paper as [10]
Succinate can be transported from mitochondria via the dicarboxylic acid transporter to the cytosol where in excess it impairs PHD activity by product inhibition, leading to HIF-1α stabilization and activation.
“Succinate can be transported from the mitochondria via the dicarboxylic acid transporter to the cytosol where in excess it impairs PHD activity (by product inhibition) leading to HIF-1α stabilization and activation.”
From Succinate is an inflammatory signal that induces IL-1β through HIF-1α (2013) · cites this paper as [10]
Complex II deficiency achieved by suppression of SdhD induces normoxic HIF-1α stabilization via accumulation of succinate without inducing a detectable increase in ROS production.
“Selak et al. reported that complex II deficiency achieved by the suppression of SdhD induces normoxic HIF-1 𝛂 stabilization via the accumulation of succinate without inducing a detectable increase in ROS production (43, 44).”
From Loss of the SdhB, but Not the SdhA, Subunit of Complex II Triggers Reactive Oxygen Species-Dependent Hypoxia-Inducible Factor Activation and Tumorigenesis (2008) · cites this paper as [43]
Decreases in Sdh activity should cause an accumulation of succinate, which can transit to the cytosol through the dicarboxylate carrier and inhibit PHD, causing HIFα stabilization through a pseudohypoxia pathway that does not require ROS.
“Decreases in Sdh activity should cause an accumulation of succinate, which can transit to the cytosol through the dicarboxylate carrier. There, it potentially can inhibit PHD and cause HIFα stabilization through a pseudohypoxia pathway that does not require ROS (43, 44).”
From Loss of the SdhB, but Not the SdhA, Subunit of Complex II Triggers Reactive Oxygen Species-Dependent Hypoxia-Inducible Factor Activation and Tumorigenesis (2008) · cites this paper as [43]
Increases in succinate represent an important contribution to the stabilization of HIFα in cells with Sdh inhibition.
“We agree that increases in succinate represent an important contribution to the stabilization of HIFα in cells with Sdh inhibition (43).”
From Loss of the SdhB, but Not the SdhA, Subunit of Complex II Triggers Reactive Oxygen Species-Dependent Hypoxia-Inducible Factor Activation and Tumorigenesis (2008) · cites this paper as [43]
PHDs are inactive at low O2 and can be inactivated by accumulation of TCA metabolites fumarate and succinate.
“PHDs are inactive at low O2 and can be inactivated by the accumulation of TCA metabolites fumarate and succinate, which may occur from mutations in the tumor suppressor genes succinate dehydrogenase subunit B or fumarate hydratase (187, 334, 384).”
From Redox regulation of mitochondrial function (2012) · cites this paper as [384]
SDH and FH loss-of-function mutations accumulate succinate and fumarate, which compete with αKG, inhibit HIF hydroxylases, and produce normoxic HIF1α activity in vitro.
“Loss-of-function mutations in SDH and FH cause a build-up of succinate and fumarate, respectively87. Accordingly, increased levels of succinate and fumarate caused by mutations in these genes can compete with αKG and inhibit activity of HIF hydroxylases and thus induce normoxic HIF1α activity in vitro88,89.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [88]
Succinate and fumarate accumulation can inhibit αKG-dependent prolyl hydroxylases, leading to stabilization of HIF-1 and activation of the HIF/hypoxia transcriptional program.
“In addition to affecting the activity of chromatin-associated αKG-dependent dioxygenases, succinate and fumarate accumulation can also inhibit αKG-dependent prolyl hydroxylases, leading to stabilization of HIF-1 and concomitant activation of the HIF/hypoxia transcriptional program (184, 185).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [185]
Succinate is also an inhibitor of HIF-1α, which has been implicated in the exaggerated production of sFlt-1 and in the pathophysiology of preeclampsia.
“However, succinate is also an inhibitor of HIF-1α(213), which has been implicated in the exaggerated production of sFlt-1 and in the pathophysiology of preeclampsia(214, 215)”
From Metformin, the Aspirin of the 21st Century: Its Role in Gestational Diabetes Mellitus, Prevention of Preeclampsia and Cancer, and the Promotion of Longevity (2017) · cites this paper as [213]
High levels of succinate and fumarate can inhibit PHD2 activity through product-mediated inhibition of PHD function, leading to HIF-1α protein stabilization under normoxic (20% O2) conditions.
“High levels of succinate and fumarate can inhibit PHD2 activity through product-mediated inhibition of PHD function, leading to HIF-1α protein stabilization under normoxic (20% O2) conditions (100, 101).”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [101]
Succinate impairs PHD2 through product inhibition.
“Succinate was initially found to impair PHD2, the α-ketoglutarate-dependent enzyme regulating HIF stability, through product inhibition (Selak et al., 2005).”
From Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012) · cites this paper as Selak et al., 2005
Elevated levels of succinate or fumarate can inhibit PHD activity.
“elevated levels of succinate or fumarate can inhibit PHD activity [65, 66]”
From Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function (2013) · cites this paper as [66]
Both succinate and fumarate are competitive PHD inhibitors, and massive accumulation of these metabolites in cells lacking SDH or FH activity elicits a hypoxic response even under oxygen-replete conditions.
“Both succinate and fumarate are competitive PHD inhibitors, and the massive accumulation of these metabolites in cells lacking SDH or FH activity elicit a hypoxic response even under oxygen-replete condition (Isaacs et al., 2005; Selak et al., 2005).”
From Cellular Metabolism and Disease: What Do Metabolic Outliers Teach Us? (2012) · cites this paper as Selak et al., 2005
Both succinate and fumarate aberrantly increase the function of hypoxia inducible factors (HIFs).
“Furthermore, both succinate and fumarate aberrantly increase the function of hypoxia inducible factors (HIFs).”
From Cellular Metabolism and Disease: What Do Metabolic Outliers Teach Us? (2012) · cites this paper as Selak et al., 2005
Hypoxia and ischemia, as well as decreased oxidative phosphorylation, drive succinate accumulation in the mitochondrial matrix.
“It should be noted that hypoxia and ischemia, as well as decreased oxidative phosphorylation, drive succinate accumulation in the mitochondrial matrix26,27.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [27]
Succinate inhibits the hydroxylation of HIF-1α by EGLN1, resulting in pseudohypoxic HIF-1α stabilization under normoxic conditions.
“Succinate inhibits the hydroxylation of HIF-1␣ by EGLN1, resulting in pseudohypoxic HIF-1␣ stabilization under normoxic conditions (10 -12).”
From Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels (2016) · cites this paper as [10]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

Di3 microscopy panel is described both with and without pVHL
Minor
The Figure 6A legend identifies panel v as the Di3 condition without pVHL. The results text instead describes the Di3 and Di4 comparisons in panels iv-vi as experiments cotransfected with HA-tagged pVHL, so the Di3 condition is inconsistent between the two descriptions.

1 of 1

Targeting of HIF-α to the von Hippel-Lindau Ubiquitylation Complex by O <sub>2</sub> -Regulated Prolyl Hydroxylation
Jaakkola, P., Mole, D. R., Tian, Y.-M., Wilson, M. I., Gielbert, J., Gaskell, S. J., Kriegsheim, A. V., Hebestreit, H. F., Mukherji, M., Schofield, C. J., et al. (2001) · Science · doi:10.1126/science.1059796 · Cited by 5,535 · cited 1× · see citing works
“In particular, elevated levels al., 2001; Jaakkola et al., 2001; Yu et al., 2001).”
Background
HIFα Targeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for O <sub>2</sub> Sensing
Ivan, M., Kondo, K., Yang, H., Kim, W., Valiando, J., Ohh, M., Salic, A., Asara, J. M., Lane, W. S., & Kaelin Jr., W. G. (2001) · Science · doi:10.1126/science.1059817 · Cited by 4,735 · cited 1× · see citing works
“, facilitate HIF-2 (cid:1) degradation in these cells, despite the fact that PHD activity is inhibited. and ascorbate, it undergoes hydroxylation and migrates faster CANCER CELL : JANUARY 2005 on SDS-PAGE (Huang et al., 2002; Ivan et al., 2001).”
Background
C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation
Epstein, A. C. R., Gleadle, J. M., McNeill, L. A., Hewitson, K. S., O'Rourke, J., Mole, D. R., Mukherji, M., Metzen, E., Wilson, M. I., Dhanda, A., et al. (2001) · Cell · doi:10.1016/s0092-8674(01)00507-4 · Cited by 3,333 · cited 1× · see citing works
“The hydroxylases (HPH1-3 or PHD1-3) (Bruick and McKnight, 2001; Epstein et al., 2001; Ivan et al., 2002).”
A conserved family of prolyl-4-hydroxylases that modify HIF
Bruick, R. K., & McKnight, S. L. (2001) · Science · doi:10.1126/science.1066373 · Cited by 2,549 · cited 1× · see citing works
“The hydroxylases (HPH1-3 or PHD1-3) (Bruick and McKnight, 2001; Epstein et al., 2001; Ivan et al., 2002).”
Regulation of angiogenesis by hypoxia: role of the HIF system
Pugh, C. W., & Ratcliffe, P. J. (2003) · Nature Medicine · doi:10.1038/nm0603-677 · Cited by 2,520 · cited 11× · see citing works
“) and ascorbate as cofactors (Kaelin, 2002; Scho-ﬁeld and Zhang, 1999).”
BackgroundMethodInfluential
A model for p53-induced apoptosis
Polyak, K., Xia, Y., Zweier, J. L., Kinzler, K. W., & Vogelstein, B. (1997) · Nature · doi:10.1038/38525 · Cited by 2,500 · cited 1× · see citing works
“The tumor suppressor p53, which is known to elevate ROS production (Polyak et al., 1997), was used as a positive control.”
Method
Oxygen sensing by HIF hydroxylases
Schofield, C. J., & Ratcliffe, P. J. (2004) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1366 · Cited by 2,068 · see citing works
Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1α during hypoxia
Chandel, N. S., McClintock, D. S., Feliciano, C. E., Wood, T. M., Melendez, J. A., Rodriguez, A. M., & Schumacker, P. T. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m001914200 · Cited by 2,000 · cited 1× · see citing works
“…c oxidase we found that hydrogen peroxide can induce HIF-1 (cid:1) levels as (complex IV), hence allocating more oxygen for PHD activity in was previously described (Chandel et al., 2000) (data not shown), we observed neither ROS generation nor a shift to a the cytosol (Hagen et al., 2003).”
Background
Asparagine Hydroxylation of the HIF Transactivation Domain: A Hypoxic Switch
Lando, D., Peet, D. J., Whelan, D. A., Gorman, J. J., & Whitelaw, M. L. (2002) · Science · doi:10.1126/science.1068592 · Cited by 1,558 · cited 1× · see citing works
“The transcriptional activity of HIF-(cid:1) is also regulated by hydroxylation of an asparaginyl residue in its C-terminal transactivation domain in a reaction catalyzed by factor inhibiting HIF (FIH) (Hewitson et al., 2002; Lando et al., 2002a,2002b).”
Background
FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor
Lando, D., Peet, D. J., Gorman, J. J., Whelan, D. A., Whitelaw, M. L., & Bruick, R. K. (2002) · Genes & Development · doi:10.1101/gad.991402 · Cited by 1,550 · see citing works
Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene
Pennacchietti, S., Michieli, P., Galluzzo, M., Mazzone, M., Giordano, S., & Comoglio, P. M. (2003) · Cancer Cell · doi:10.1016/s1535-6108(03)00085-0 · Cited by 1,311 · cited 1× · see citing works
“mutations promotes metastasis by inducing the expression of met and CXCR4 (Pennacchietti et al., 2003; Staller et al., 2003).”
Background
Differential Function of the Prolyl Hydroxylases PHD1, PHD2, and PHD3 in the Regulation of Hypoxia-inducible Factor
Appelhoff, R. J., Tian, Y.-M., Raval, R. R., Turley, H., Harris, A. L., Pugh, C. W., Ratcliffe, P. J., & Gleadle, J. M. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m406026200 · Cited by 1,108 · cited 2× · see citing works
“In vitro translated HA-tagged ODD domain was ity of HIF-1 and HIF-2 , respectively (Appelhoff et al., 2004), used as a substrate, and cell extracts were used as a source of and these enzymes may exhibit differences in their response to PHD activity.”
Method
HIF-1 and tumor progression: pathophysiology and therapeutics
Semenza, G. L. (2002) · Trends in Molecular Medicine · doi:10.1016/s1471-4914(02)02317-1 · Cited by 1,060 · cited 2× · see citing works
“This posttranslational modiﬁcation is catalyzed by the HIF-(cid:1) -prolyl HIF transcription factor, a heterodimer comprised of HIF-(cid:1) and HIF-(cid:2) subunits (Pugh and Ratcliffe, 2003; Semenza, 2002).”
Background
Architecture of succinate dehydrogenase and reactive oxygen species generation
Yankovskaya, V., Horsefield, R., Törnroth, S., Luna-Chavez, C., Miyoshi, H., Léger, C., Byrne, B., Cecchini, G., & Iwata, S. (2003) · Science · doi:10.1126/science.1079605 · Cited by 927 · see citing works
Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors
He, W., Miao, F. J.-P., Lin, D. C.-H., Schwandner, R. T., Wang, Z., Gao, J., Chen, J.-L., Tian, H., & Ling, L. (2004) · Nature · doi:10.1038/nature02488 · Cited by 909 · cited 1× · see citing works
“…inﬁltrating form. protein-coupled receptor, suggesting that succinate can also It is frequently hypothesized in the literature that ROS gener-be released from cells under some physiological/pathological ation due to SDH mutations may mediate HIF-1 (cid:1) induction circumstances (He et al., 2004).”
Background
Distinct Clinical Features of Paraganglioma Syndromes Associated With <EMPH TYPE="ITAL">SDHB</EMPH> and <EMPH TYPE="ITAL">SDHD</EMPH> Gene Mutations
Neumann, H. P. H. (2004) · JAMA · doi:10.1001/jama.292.8.943 · Cited by 893 · cited 1× · see citing works
“Therefore, in tumors carrying VHL mutations that can no noma and papillary thyroid cancer (Neumann et al., 2004), and longer bind to and destabilize HIF-1 (cid:1) , HIF-1 (cid:1) is stabilized even downregulation of SDHD was reported in gastric and colon under normoxic conditions (Kaelin, 2002).…”
Background
Chemokine receptor CXCR4 downregulated by von Hippel–Lindau tumour suppressor pVHL
Staller, P., Sulitkova, J., Lisztwan, J., Moch, H., Oakeley, E. J., & Krek, W. (2003) · Nature · doi:10.1038/nature01874 · Cited by 870 · see citing works
Molecular basis of the VHL hereditary cancer syndrome
Kaelin, W. G. (2002) · Nature Reviews Cancer · doi:10.1038/nrc885 · Cited by 865 · cited 3× · see citing works
“Since pVHL binding to the ODD domain is dependent on PHD activity (Kaelin, 2002; Safran and Kaelin, 2003), these results indicate that inhibiting SDH activity in cells results in decreased PHD activity. puriﬁed HA-pVHL protein and GFP-ODD/HA-pVHL complexes were detected by an anti-HA antibody…”
Background
HIF-1α binding to VHL is regulated by stimulus-sensitive proline hydroxylation
Yu, F., White, S. B., Zhao, Q., & Lee, F. S. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.181341498 · Cited by 796 · cited 1× · see citing works
“In particular, elevated levels al., 2001; Jaakkola et al., 2001; Yu et al., 2001).”
Background
Structure of an HIF-1α-pVHL Complex: Hydroxyproline Recognition in Signaling
Min, J.-H., Yang, H., Ivan, M., Gertler, F., Kaelin, W. G., & Pavletich, N. P. (2002) · Science · doi:10.1126/science.1073440 · Cited by 765 · cited 2× · see citing works
“HIF- subunit is the oxygen-inducible component of the orders of magnitude (Hon et al., 2002; Min et al., 2002).”
Background
Structural basis for the recognition of hydroxyproline in HIF-1α by pVHL
Hon, W.-C., Wilson, M. I., Harlos, K., Claridge, T. D. W., Schofield, C. J., Pugh, C. W., Maxwell, P. H., Ratcliffe, P. J., Stuart, D. I., & Jones, E. Y. (2002) · Nature · doi:10.1038/nature00767 · Cited by 751 · cited 1× · see citing works
“HIF-(cid:1) subunit is the oxygen-inducible component of the orders of magnitude (Hon et al., 2002; Min et al., 2002).”
Background
[42]Assessment of mitochondrial oxidative phosphorylation in patient muscle biopsies, lymphoblasts, and transmitochondrial cell lines
Trounce, I. A., Kim, Y. L., Jun, A. S., & Wallace, D. C. (1996) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(96)64044-0 · Cited by 749 · cited 1× · see citing works
“…(DCIP) Next, we compared HIF-1 (cid:1) protein levels in SDH-inhibited were used as electron donor and acceptor, respectively, to cells under normoxic conditions to HIF-1 (cid:1) physiological levels spectrophotometrically measure SDH activity (Trounce et al., under hypoxic conditions.”
Method
Hypoxia-inducible factor (HIF) asparagine hydroxylase is identical to factor inhibiting HIF (FIH) and is related to the cupin structural family
Hewitson, K. S., McNeill, L. A., Riordan, M. V., Tian, Y.-M., Bullock, A. N., Welford, R. W., Elkins, J. M., Oldham, N. J., Bhattacharya, S., Gleadle, J. M., et al. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.c200273200 · Cited by 719 · cited 3× · see citing works
“For studying reduced and total glutathione levels, cell lysates were regulate HIF activity by modulating another (cid:1) -ketoglutarate de-prepared using a lysis buffer (Cell Signaling) freshly supplemented with pendent dioxygenase, FIH, thereby altering the ability of HIF-1 (cid:1) protease inhibitor cocktail for mam…”
Background
HIF-1-dependent regulation of hypoxic induction of the cell death factors BNIP3 and NIX in human tumors.
Sowter, H., Ratcliffe, P. J., Watson, P. H., Greenberg, A. H., & Harris, A. L. (2001) · PubMed · Cited by 711 · see citing works
Redistribution of Intracellular Oxygen in Hypoxia by Nitric Oxide: Effect on HIF1α
Hagen, T., Taylor, C. T., Lam, F., & Moncada, S. (2003) · Science · doi:10.1126/science.1088805 · Cited by 704 · cited 2× · see citing works
“, 2000) (data not shown), we observed neither ROS generation nor a shift to a the cytosol (Hagen et al., 2003).”
Background
Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor
Ivan, M., Haberberger, T., Gervasi, D. C., Michelson, K. S., Günzler, V., Kondo, K., Yang, H., Sorokina, I., Conaway, R. C., Conaway, J. W., et al. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.192342099 · Cited by 561 · cited 1× · see citing works
“The hydroxylases (HPH1-3 or PHD1-3) (Bruick and McKnight, 2001; Epstein et al., 2001; Ivan et al., 2002).”
Structural and mechanistic studies on 2-oxoglutarate-dependent oxygenases and related enzymes
Schofield, C. J., & Zhang, Z. (1999) · Current Opinion in Structural Biology · doi:10.1016/s0959-440x(99)00036-6 · Cited by 408 · cited 2× · see citing works
“The PHD isozymes belong to the Fe and -ketoglutarate-dependent family of dioxygenases that split molecular oxygen to hydroxylate their substrates and, in parallel, oxidize and decarboxylate -ketoglutarate to succinate (Schofield and Zhang, 1999).”
Background
A role for mitochondrial enzymes in inherited neoplasia and beyond
Eng, C., Kiuru, M., Fernandez, M. J., & Aaltonen, L. A. (2003) · Nature Reviews Cancer · doi:10.1038/nrc1013 · Cited by 392 · cited 3× · see citing works
“…ubiquitin ligase SDH genes are associated with the development of pheochro-complex that binds to the oxygen-dependent degradation mocytoma and paraganglioma (Baysal, 2003; Eng et al., 2003; (ODD) domain of HIF-(cid:1) in an oxygen-dependent manner and Pollard et al., 2003; Rustin and Rotig, 2002).”
Background
HIF hydroxylation and the mammalian oxygen-sensing pathway
Safran, M., & Kaelin, W. G. (2003) · Journal of Clinical Investigation · doi:10.1172/jci200318181 · Cited by 365 · see citing works
The R22X mutation of the SDHD gene in hereditary paraganglioma abolishes the enzymatic activity of complex II in the mitochondrial respiratory chain and activates the hypoxia pathway
Gimenez-Roqueplo, A.-P., Favier, J., Rustin, P., Mourad, J.-J., Plouin, P.-F., Corvol, P., Rötig, A., & Jeunemaitre, X. (2001) · The American Journal of Human Genetics · doi:10.1086/324413 · Cited by 364 · cited 2× · see citing works
“…(HIF-1 (cid:1) ) in nuclei and the induction of hypoxia-inducible genes were observed in paragangli-to human HIF-1 (cid:1) ) enables formation of two hydrogen bonds to pVHL and increases the binding of pVHL to HIF-(cid:1) by several oma carrying an SDHD mutation (Gimenez-Roqueplo et al., 2001).”
Background
HIF hydroxylation and the mammalian oxygen-sensing pathway
Safran, M., & Kaelin, W. G. (2003) · Journal of Clinical Investigation · doi:10.1172/jci18181 · Cited by 363 · cited 3× · see citing works
“This sug-mimetic compound (Safran and Kaelin, 2003), for 3 hr. Hypoxia geststhat SDHactivityin transfectedcellsis severelydiminished or hypoxic mimetic treatment induced higher levels of HIF-1 (cid:1) at the time of analysis.”
BackgroundMethod
The serine/threonine kinase Pim-2 is a transcriptionally regulated apoptotic inhibitorPreprint
Fox, C. J., Hammerman, P. S., Cinalli, R. M., Master, S. R., Chodosh, L. A., & Thompson, C. B. (2003) · Genes & Development · doi:10.1101/gad.1105003 · Cited by 334 · cited 2× · see citing works
“Extracts were evaporated to dryness under nitrowith the U6 promoter, as previously described (Fox et al., 2003).”
MethodSelf-citation
Sequence determinants in hypoxia-inducible factor-1α for hydroxylation by the prolyl hydroxylases PHD1, PHD2, and PHD3
Huang, J., Zhao, Q., Mooney, S. M., & Lee, F. S. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m206955200 · Cited by 307 · cited 4× · see citing works
“, facilitate HIF-2 (cid:1) degradation in these cells, despite the fact that PHD activity is inhibited. and ascorbate, it undergoes hydroxylation and migrates faster CANCER CELL : JANUARY 2005 on SDS-PAGE (Huang et al., 2002; Ivan et al., 2001).”
BackgroundInfluential
Untitled work
(2002) · PubMed · Cited by 296 · see citing works
A defect in the cytochrome b large subunit in complex II causes both superoxide anion overproduction and abnormal energy metabolism in Caenorhabditis elegans
Senoo-Matsuda, N., Yasuda, K., Tsuda, M., Ohkubo, T., Yoshimura, S., Nakazawa, H., Hartman, P. S., & Ishii, N. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m104718200 · Cited by 271 · cited 1× · see citing works
“It is noteworthy that, in addition superoxide ions (Senoo-Matsuda et al., 2001).”
Background
Mechanism of the Prolyl Hydroxylase Reaction: 2. Kinetic Analysis of the Reaction Sequence
MYLLYLÄ, R., TUDERMAN, L., & KIVIRIKKO, K. I. (1977) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1977.tb11889.x · Cited by 263 · cited 1× · see citing works
“Furthermore,succinatehasbeen showntoinhibitsome (cid:1) -ketoglutarate-dependent oxygenases, including procollagenprolyl hydroxylaseand thymine-7-hydrox-ylase (Holme, 1975; Myllyla et al., 1977).”
Background
Essential role of complex II of the respiratory chain in hypoxia-induced ROS generation in the pulmonary vasculature
Paddenberg, R., Ishaq, B., Goldenberg, A., Faulhammer, P., Rose, F., Weissmann, N., Braun-Dullaeus, R. C., & Kummer, W. (2003) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00149.2002 · Cited by 184 · cited 2× · see citing works
“We describe a direct signaling pathway that links mitochon-under normoxic conditions and is unlikely to be catalyzed by drial dysfunction to tumorigenesis, providing a mechanistic link mutated SDH (Paddenberg et al., 2003).”
Background
The TCA cycle and tumorigenesis: the examples of fumarate hydratase and succinate dehydrogenase
Pollard, P., Wortham, N., & Tomlinson, I. (2003) · Annals of Medicine · doi:10.1080/07853890310018458 · Cited by 159 · cited 4× · see citing works
“…ubiquitin ligase SDH genes are associated with the development of pheochro-complex that binds to the oxygen-dependent degradation mocytoma and paraganglioma (Baysal, 2003; Eng et al., 2003; (ODD) domain of HIF-(cid:1) in an oxygen-dependent manner and Pollard et al., 2003; Rustin and Rotig, 2002).”
BackgroundInfluential
Inborn errors of complex II – Unusual human mitochondrial diseases
Rustin, P., & Rötig, A. (2002) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/s0005-2728(01)00228-6 · Cited by 135 · cited 3× · see citing works
“…ubiquitin ligase SDH genes are associated with the development of pheochro-complex that binds to the oxygen-dependent degradation mocytoma and paraganglioma (Baysal, 2003; Eng et al., 2003; (ODD) domain of HIF-(cid:1) in an oxygen-dependent manner and Pollard et al., 2003; Rustin and Rotig, 2002).”
Background
Hypoxia-inducible Factor-2α (HIF-2α) Is Involved in the Apoptotic Response to Hypoglycemia but Not to Hypoxia
Brusselmans, K., Bono, F., Maxwell, P. H., Dor, Y., Dewerchin, M. A., Collen, D., Herbert, J., & Carmeliet, P. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.c100428200 · Cited by 112 · cited 1× · see citing works
“It is noteworthy that in contrast to oxia or hypoglycemia (Brusselmans et al., 2001).”
Background
On the association of succinate dehydrogenase mutations with hereditary paraganglioma
Baysal, B. E. (2003) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2003.08.004 · Cited by 106 · cited 18× · see citing works
“These results suggest suggested a mechanism for ROS production at the FAD site that in SDH-inhibited cells, PHD activity is reduced.”
BackgroundInfluential
Classification of Dukes' B and C colorectal cancers using expression arrays
Frederiksen, C. M., Knudsen, S., Laurberg, S., & Ørntoft, T. F. (2003) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-003-0434-x · Cited by 95 · cited 1× · see citing works
“…Dukes’ stage C colorectal cancer, as compared to vated in tumors with SDH mutations (P. Rustin; personal com-the conﬁned Dukes’ stage B tumors (Frederiksen et al., 2003). munication) suggests that our model is more relevant for human Therefore, it is plausible that the succinate signaling…”
Background
Kinetic study of thymine 7-hydroxylase from Neurospora crassa
Holme, E. (1975) · Biochemistry · doi:10.1021/bi00693a033 · Cited by 74 · cited 1× · see citing works
“Furthermore,succinatehasbeen showntoinhibitsome (cid:1) -ketoglutarate-dependent oxygenases, including procollagenprolyl hydroxylaseand thymine-7-hydrox-ylase (Holme, 1975; Myllyla et al., 1977).”
Background
Reduced expression and loss of heterozygosity of the SDHD gene in colorectal and gastric cancer
Habano, W., Sugai, T., Nakamura, S., Uesugi, N., Higuchi, T., Terashima, M., & Horiuchi, S. (2003) · Oncology Reports · doi:10.3892/or.10.5.1375 · Cited by 64 · see citing works
The TCA cycle and tumorigenesis
Pollard, P. J., Wortham, N. C., & Tomlinson, I. P. M. (2003) · Annals of Medicine · Cited by 1 · see citing works

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Sorted by citations

Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation
Vander Heiden, M. G., Cantley, L. C., & Thompson, C. B. (2009) · Science · doi:10.1126/science.1160809 · Cited by 16,197 · see citing works
Self-citation
Genetics of Food Intake Self-Regulation in Childhood: Literature Review and Research Opportunities
Faith, M. S., Carnell, S., & Kral, T. V. E. (2013) · Human Heredity · doi:10.1159/000353879 · Cited by 7,628 · see citing works
The emerging hallmarks of cancer metabolism
Pavlova, N. N., & Thompson, C. B. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2015.12.006 · Cited by 5,926 · see citing works
Self-citation
Regulation of cancer cell metabolism
Cairns, R. A., Harris, I. S., & Mak, T. W. (2011) · Nature Reviews Cancer · doi:10.1038/nrc2981 · Cited by 4,744 · see citing works
Succinate is an inflammatory signal that induces IL-1β through HIF-1α
Tannahill, G. M., Curtis, A. M., Adamik, J., Palsson-McDermott, E. M., McGettrick, A. F., Goel, G., Frezza, C., Bernard, N. J., Kelly, B., Foley, N. H., et al. (2013) · Nature · doi:10.1038/nature11986 · Cited by 4,176 · see citing works
Self-citation
The Biology of Cancer: Metabolic Reprogramming Fuels Cell Growth and Proliferation
DeBerardinis, R. J., Lum, J. J., Hatzivassiliou, G., & Thompson, C. B. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2007.10.002 · Cited by 4,088 · see citing works
“…complex; mTOR, mammalian target of rapamycin; glc-6-P, glucose-6-phosphate; 3-PG, 3-phosphoglycerate; PDK1, pyruvate dehydrogenase kinase 1; SDH, succinate dehydrogenase; FH, fumarate hydratase; HIF-1 a , hypoxia-inducible factor 1 a ; VHL, von Hippel-Lindau. et al., 2007; Selak et al., 2005).”
Self-citation
Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway.
Kaelin, W. G., & Ratcliffe, P. J. (2008) · Molecular Cell · doi:10.1016/j.molcel.2008.04.009 · Cited by 3,251 · see citing works
“It has also been reported that defects in SDH B increase ROS production and that ROS enhance the stabilization of HIFa produced by succinate accumulation (Guzy et al., 2007), although the importance of ROS in this setting has been disputed (Lee et al., 2005; Selak et al., 2006).”
Background
Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate
Ward, P. S., & Thompson, C. B. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.02.014 · Cited by 3,233 · see citing works
“Succinate was initially found to impair PHD2, the a-ketoglutarate-dependent enzyme regulating HIF stability, through product inhibition (Selak et al., 2005).”
BackgroundSelf-citation
Mitochondrial TCA cycle metabolites control physiology and disease
Martínez-Reyes, I., & Chandel, N. S. (2020) · Nature Communications · doi:10.1038/s41467-019-13668-3 · Cited by 2,813 · see citing works
Oncometabolite 2-Hydroxyglutarate Is a Competitive Inhibitor of α-Ketoglutarate-Dependent Dioxygenases
Xu, W., Yang, H., Liu, Y., Yang, Y., Wang, P., Kim, S.-H., Ito, S., Yang, C., Wang, P., Xiao, M.-T., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2010.12.014 · Cited by 2,875 · see citing works
“Mutations targeting FH and SDH lead to similar increase in the PHD substrate, HIF-1a (Isaacs et al., 2005; Pollard et al., 2005; Selak et al., 2005).”
Background
Metabolic reprogramming and cancer progression
Faubert, B., Solmonson, A., & DeBerardinis, R. J. (2020) · Science · doi:10.1126/science.aaw5473 · Cited by 2,740 · see citing works
“Metabolite accumulation in the setting of dysfunctional mitochondria can inhibit VHL-dependent degradation of hypoxia-inducible factor-a (HIF-a) subunits, creating a pseudohypoxic state that mimics VHL loss (14).”
Background
Cancer cell metabolism: warburg and beyond
Hsu, P. P., & Sabatini, D. M. (2008) · Cell · doi:10.1016/j.cell.2008.08.021 · Cited by 2,452 · see citing works
“…has been proposed that loss of succinate dehydrogenase and fumarate hydratase causes an accumulation of succinate or fumarate, respectively, leading to inhibition of the prolyl hydroxylases that mark HIF for VHL-mediated degradation (Isaacs et al., 2005; Pollard et al., 2005; Selak et al., 2005).”
Background
Understanding the Intersections between Metabolism and Cancer Biology
Heiden, M. G. V., & DeBerardinis, R. J. (2017) · Cell · doi:10.1016/j.cell.2016.12.039 · Cited by 2,316 · see citing works
“Like D-2HG, these dicarboxylic acids interfere with dioxygenase function (Sciacovelli et al., 2016; Selak et al., 2005; Xiao et al., 2012).”
Role of Mitochondria in Ferroptosis
Gao, M., Yi, J., Zhu, J., Minikes, A. M., Monian, P., Thompson, C. B., & Jiang, X. (2019) · Molecular Cell · doi:10.1016/j.molcel.2018.10.042 · Cited by 2,120 · see citing works
“FH defect leads to aberrant accumulation of fumarate, which in turn inactivates prolyl hydroxylases and thus stabilizes hypoxia-inducible factor (HIF)-1α (Isaacs et al., 2005; Selak et al., 2005).”
BackgroundSelf-citation
Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics
Semenza, G. L. (2010) · Oncogene · doi:10.1038/onc.2009.441 · Cited by 1,712 · see citing works
Mitochondrial ROS in cancer: initiators, amplifiers or an Achilles' heel?
Sabharwal, S. S., & Schumacker, P. T. (2014) · Nature reviews. Cancer · doi:10.1038/nrc3803 · Cited by 1,643 · see citing works
The Obesity-Associated FTO Gene Encodes a 2-Oxoglutarate-Dependent Nucleic Acid Demethylase
Gerken, T., Girard, C. A. J., Tung, Y. L., Webby, C. J., Saudek, V., Hewitson, K. S., Yeo, G. S. H., McDonough, M. A., Cunliffe, S. L., McNeill, L. A., et al. (2007) · Science · doi:10.1126/science.1151710 · Cited by 1,519 · see citing works
Glycolysis inhibition for anticancer treatment
Pelicano, H., Martin, D. S., Xu, R., & Huang, P. (2006) · Oncogene · doi:10.1038/sj.onc.1209597 · Cited by 1,516 · see citing works
“A recent study showed that inhibition of SDH causes an accumulation of succinate, which suppresses HIF-1a prolyl hydroxylases in the cytosol, leading to stabilization and activation of the oncogenic molecule HIF-1a (Selak et al., 2005).”
BackgroundInfluential
Pyruvate kinase M2 regulates Hif-1α activity and IL-1β induction and is a critical determinant of the Warburg effect in LPS-activated macrophages
Palsson-McDermott, E. M., Curtis, A. M., Goel, G., Lauterbach, M. A. R., Sheedy, F. J., Gleeson, L. E., van den Bosch, M. W. M., Quinn, S. R., Domingo-Fernandez, R., Johnston, D. G. W., et al. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2014.12.005 · Cited by 1,397 · see citing works
“This phenomenon, which has been described as ‘pseudo hypoxia’ takes place when excess succinate is transported out of the mitochondria into the cytosol where it can impair the activity of prolylhydroxylases (PHD) leading to stabilization and activation of Hif-1α (Selak et al., 2005).”
HIF-1: upstream and downstream of cancer metabolism
Semenza, G. L. (2009) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2009.10.009 · Cited by 1,381 · see citing works
Fueling Immunity: Insights into Metabolism and Lymphocyte Function
Pearce, E. L., Poffenberger, M. C., Chang, C.-H., & Jones, R. G. (2013) · Science · doi:10.1126/science.1242454 · Cited by 1,363 · see citing works
“mediated inhibition of PHD function, leading to HIF-1a protein stabilization under normoxic (20% O2) conditions (100, 101).”
Background
Lipid metabolism in cancer
Santos, C. R., & Schulze, A. (2012) · FEBS Journal · doi:10.1111/j.1742-4658.2012.08644.x · Cited by 1,344 · see citing works
HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations
Semenza, G. L. (2013) · Journal of Clinical Investigation · doi:10.1172/jci67230 · Cited by 1,335 · see citing works
“…in VHL directly block the ubiquitination of HIF-α subunits, mutations in the genes encoding succinate dehydrogenase (SDH) and fumarate hydratase (FH) block ubiquitination indirectly by increasing the concentration of TCA cycle intermediates that inhibit prolyl hydroxylase activity (91–93).”
Cellular Adaptation to Hypoxia through Hypoxia Inducible Factors and beyond
Lee, P., Chandel, N. S., & Simon, M. C. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-0227-y · Cited by 1,272 · see citing works
Self-citation
Cancer's Molecular Sweet Tooth and the Warburg Effect
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“In particular, prolyl hydroxylation of HIF-1a requires a-ketoglutarate as a substrate, which is converted to succinate, such that deficiency of SDH or FH decreases a-ketoglutarate or increases succinate, thereby inhibiting the degradation of HIF-1 (12).”
Background
Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors
Xiao, M., Yang, H., Xu, W., Ma, S., Lin, H., Zhu, H., Liu, L., Liu, Y., Yang, C., Xu, Y., et al. (2012) · Genes & Development · doi:10.1101/gad.191056.112 · Cited by 1,188 · see citing works
Hypoxia-Induced Angiogenesis: Good and Evil
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Oxygen Sensing, Hypoxia-Inducible Factors, and Disease Pathophysiology
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Tumor suppressors and cell metabolism: a recipe for cancer growth
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Self-citation
The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases
Chowdhury, R., Yeoh, K. K., Tian, Y., Hillringhaus, L., Bagg, E. A., Rose, N. R., Leung, I. K. H., Li, X. S., Woon, E. C. Y., Yang, M., et al. (2011) · The EMBO Reports · doi:10.1038/embor.2011.43 · Cited by 1,035 · see citing works
“The HIF hydroxylases function as negative regulators of HIFmediated transcription (Isaacs et al, 2005; Selak et al, 2005; Hewitson et al, 2007); thus, increased levels of succinate and fumarate are thought to promote tumour growth by inhibition of the HIF hydroxylases.”
Background
Glutamine reliance in cell metabolism
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Integration of Oxygen Signaling at the Consensus HRE
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Targeting Metabolism for Cancer Therapy
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“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript (Hewitson et al., 2007; Pollard et al., 2005; Selak et al., 2005).”
Background
SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways
Park, J., Chen, Y., Tishkoff, D. X., Peng, C., Tan, M., Dai, L., Xie, Z., Zhang, Y., Zwaans, B. M. M., Skinner, M. E., et al. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.06.001 · Cited by 1,000 · see citing works
“Elevated succinate levels can lead to epigenetic dysregulation (Cervera et al., 2009; Smith et al., 2007).”
Background
HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: Novel role of fumarate in regulation of HIF stability
Isaacs, J. S., Jung, Y. J., Mole, D. R., Lee, S., Torres-Cabala, C., Chung, Y.-L., Merino, M., Trepel, J., Zbar, B., Toro, J., et al. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.06.017 · Cited by 958 · see citing works
“Succinate also upregulates HIF by inhibiting its proline hydroxylation (Selak et al., 2005), but in vitro enzyme kinetic analysis proves it to be a weaker antagonist of 2-OG, a finding in keeping with its reduced potency (relative to fumarate) in causing intracellular HIF accumulation in A549 cells.”
BackgroundInfluential
Mitochondria in the Regulation of Innate and Adaptive Immunity
Weinberg, S. E., Sena, L. A., & Chandel, N. S. (2015) · Immunity · doi:10.1016/j.immuni.2015.02.002 · Cited by 960 · see citing works
“, 2013), an effect that has previously been reported to occur in tumors (Selak et al., 2005).”
Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism
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Cancer Cell Metabolism: One Hallmark, Many Faces
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Hypoxia-Inducible Factor 1 (HIF-1) Pathway
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Influence of Metabolism on Epigenetics and Disease
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“For example, the HIF1a transcription factor accumulates in SDH and FH mutant tumors, presumably due to inhibition of the EglN prolyl hydroxylases (Dahia et al., 2005; Isaacs et al., 2005; Pollard et al., 2005, 2007; Selak et al., 2005).”
Advances in Hypoxia-Inducible Factor Biology
Choudhry, H., & Harris, A. L. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.10.005 · Cited by 873 · see citing works
Accumulation of Krebs cycle intermediates and over-expression of HIF1α in tumours which result from germline FH and SDH mutations
Pollard, P. J., Brière, J. J., Alam, N. A., Barwell, J., Barclay, E., Wortham, N. C., Hunt, T., Mitchell, M., Olpin, S., Moat, S. J., et al. (2005) · Human Molecular Genetics · doi:10.1093/hmg/ddi227 · Cited by 865 · see citing works
“Recently, support has been provided using an in vitro system for dysfunction of the Krebs cycle leading to the stabilization of HIF (27).”
BackgroundInfluential
Cellular Metabolism and Disease: What Do Metabolic Outliers Teach Us?
DeBerardinis, R. J., & Thompson, C. B. (2012) · Cell · doi:10.1016/j.cell.2012.02.032 · Cited by 858 · see citing works
Self-citation
Oncogenic BRAF Regulates Oxidative Metabolism via PGC1α and MITF
Haq, R., Shoag, J., Andreu-Perez, P., Yokoyama, S., Edelman, H., Rowe, G. C., Frederick, D. T., Hurley, A. D., Nellore, A., Kung, A. L., et al. (2013) · Cancer Cell · doi:10.1016/j.ccr.2013.02.003 · Cited by 818 · see citing works
Apoptotic Pathways: Ten Minutes to Dead
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The role of HIF in immunity and inflammation
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SDH mutations establish a hypermethylator phenotype in paraganglioma
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“Succinate and fumarate can activate the oncogenic HIF pathway by inhibiting HIF prolyl-hydroxylases (Brière et al., 2005; Selak et al., 2005).”
Background
HIF1α and metabolic reprogramming in inflammation
Corcoran, S. E., & O'Neill, L. A. J. (2016) · Journal of Clinical Investigation · doi:10.1172/jci84431 · Cited by 789 · see citing works
Human mitochondrial DNA: roles of inherited and somatic mutations
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A Unifying Mechanism for Mitochondrial Superoxide Production during Ischemia-Reperfusion Injury
Chouchani, E. T., Pell, V. R., James, A. M., Work, L. M., Saeb-Parsy, K., Frezza, C., Krieg, T., & Murphy, M. P. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2015.12.009 · Cited by 752 · see citing works
Succinate: a metabolic signal in inflammation
Mills, E., & O’Neill, L. A. J. (2014) · Trends in Cell Biology · doi:10.1016/j.tcb.2013.11.008 · Cited by 741 · see citing works
Metabolic targets for cancer therapy
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Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells
Yuneva, M., Zamboni, N., Oefner, P., Sachidanandam, R., & Lazebnik, Y. (2007) · The Journal of Cell Biology · doi:10.1083/jcb.200703099 · Cited by 690 · see citing works
“Some of the Krebs cycle intermediates, such as fumarate, succinate, and 2-oxoglutarate, can function as messenger and cofactor molecules directly regulating activity of enzymes and thereby contributing to regulation of gene transcription and/or tumorigenesis (Selak et al., 2005; Chen et al., 2006).”
Background
Analysis of cancer metabolism by imaging hyperpolarized nuclei: prospects for translation to clinical research
Kurhanewicz, J., Vigneron, D. B., Brindle, K., Chekmenev, E. Y., Comment, A., Cunningham, C. H., DeBerardinis, R. J., Green, G. G., Leach, M. O., Rajan, S. S., et al. (2011) · Neoplasia · doi:10.1593/neo.101102 · Cited by 681 · see citing works
“[24] Selak MA, Armour SM, MacKenzie ED, Boulahbel H, Watson DG, Mansfield”
Background
Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer
King, A., Selak, M. A., & Gottlieb, E. (2006) · Oncogene · doi:10.1038/sj.onc.1209594 · Cited by 672 · see citing works
“Although both molecules were shown to mediate HIF induction (Isaacs et al., 2005; Selak et al., 2005), it is possible that they inhibit different PHDs with different efficiency.”
BackgroundInfluentialSelf-citation
SDHA is a tumor suppressor gene causing paraganglioma
Burnichon, N., Brière, J.-J., Libé, R., Vescovo, L., Rivière, J., Tissier, F., Jouanno, E., Jeunemaı̂tre, X., Bénit, P., Tzagoloff, A., et al. (2010) · Human Molecular Genetics · doi:10.1093/hmg/ddq206 · Cited by 645 · see citing works
“SDHD, SDHB and SDHC (SDHx) mutations cause a cascade of molecular events leading to the abnormal stabilization of hypoxia-inducible factors (HIF) under normoxic conditions (2) or pseudo-hypoxia (via inactivation of SDH, accumulation of succinate, inhibition of prolyl-4-hydroxylases and subsequent impairment of HIF hyd…”
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Metabolic control of cell death
Green, D. R., Galluzzi, L., & Kroemer, G. (2014) · Science · doi:10.1126/science.1250256 · Cited by 661 · see citing works
How the Warburg effect supports aggressiveness and drug resistance of cancer cells?
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Adaptive and maladaptive cardiorespiratory responses to continuous and intermittent hypoxia mediated by hypoxia-inducible factors 1 and 2
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“Metabolite induction of HIF-1 results from inhibition of PHD2 activity (114, 131, 162, 201, 296).”
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Mitochondrial tumour suppressors: a genetic and biochemical update
Gottlieb, E., & Tomlinson, I. P. M. (2005) · Nature reviews. Cancer · doi:10.1038/nrc1737 · Cited by 617 · see citing works
“Recently, a novel pathway that links the inhibition of SDH to the induction of hypoxia-inducible factor (HIF) was identifie”
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Mitochondrial dysfunction resulting from loss of cytochrome c impairs cellular oxygen sensing and hypoxic HIF-α activation
Mansfield, K. D., Guzy, R. D., Pan, Y., Young, R. M., Cash, T. P., Schumacker, P. T., & Simon, M. C. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2005.05.003 · Cited by 606 · see citing works
Self-citation
Hypoxia, oxidative stress and inflammation
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Redox regulation of mitochondrial function
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Targeting immunometabolism as an anti-inflammatory strategy
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“First described as an oncometabolite, succinate was identified as a driver of the Warburg effect by inhibition of prolyl hydroxylases leading to reduced hydroxylation and hence stabilization and activation of the transcription factor Hif-1α.(167) The central role of succinate in immune cell function first came from th…”
Background
Mitochondria as playmakers of apoptosis, autophagy and senescence
Abate, M., Festa, A., Falco, M., Lombardi, A., Luce, A., Grimaldi, A., Zappavigna, S., Sperlongano, P., Irace, C., Caraglia, M., et al. (2019) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2019.05.022 · Cited by 543 · see citing works
Glucose metabolism and cancer
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Pheochromocytoma and paraganglioma pathogenesis: learning from genetic heterogeneity
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Succinate, an intermediate in metabolism, signal transduction, ROS, hypoxia, and tumorigenesis.
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The Warburg effect then and now: From cancer to inflammatory diseases
Pålsson‐McDermott, E. M., & O'Neill, L. A. J. (2013) · BioEssays · doi:10.1002/bies.201300084 · Cited by 538 · see citing works
“Succinate elevation from the TCA cycle has a negative feedback effect on PHDs, hence stabilizing Hif-1a [19].”
Background
Cancer-Derived Succinate Promotes Macrophage Polarization and Cancer Metastasis via Succinate Receptor
Wu, J.-Y., Huang, T., Hsieh, Y.-T., Wang, Y., Yen, C.-C., Lee, G.-L., Yeh, C., Peng, Y., Kuo, Y.-Y., Wen, H.-T., et al. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.10.023 · Cited by 542 · see citing works
Neuronal apoptosis linked to EglN3 prolyl hydroxylase and familial pheochromocytoma genes: developmental culling and cancer
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“For example, increased HIF activity has been observed in 293T human embryonic kidney cells treated with SDH inhibitors (Selak et al., 2005), in pheochromocytomas linked to SDH mutations (Gi-”
Background
Regulation and function of the mammalian tricarboxylic acid cycle
Arnold, P. K., & Finley, L. W. S. (2023) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.102838 · Cited by 535 · see citing works
“In addition to affecting the activity of chromatin-associated αKG-dependent dioxygenases, succinate and fumarate accumulation can also inhibit αKG-dependent prolyl hydroxylases, leading to stabilization of HIF-1 and concomitant activation of the HIF/hypoxia transcriptional program (184, 185).”
Background
Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels
Cordes, T., Wallace, M., Michelucci, A., Divakaruni, A. S., Sapcariu, S. C., Sousa, C., Koseki, H., Cabrales, P., Murphy, A. N., Hiller, K., et al. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.685792 · Cited by 526 · see citing works
Altered metabolism in cancer: insights into energy pathways and therapeutic targets
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“Loss of SDH function leads to succinate accumulation, which inhibits alpha-ketoglutarate-dependent dioxygenases and stabilizes HIFs, promoting tumorigenesis [228, 229].”
Background
Inhibition of Hypoxia-inducible Factor (HIF) Hydroxylases by Citric Acid Cycle Intermediates
Koivunen, P., Hirsilä, M., Remes, A. M., Hassinen, I. E., Kivirikko, K. I., & Myllyharju, J. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m610415200 · Cited by 521 · see citing works
Metabolism of tissue macrophages in homeostasis and pathology
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“Succinate accumulation stabilizes hypoxia-inducible factor (HIF)-1α, promoting a second wave of sustained metabolic reprogramming via gene expression programs [19, 38].”
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Mitochondrial Dysfunction in Cancer
Boland, M. L., Chourasia, A. H., & Macleod, K. F. (2013) · Frontiers in Oncology · doi:10.3389/fonc.2013.00292 · Cited by 502 · see citing works
“Thus, the downstream consequences of increased fumarate, succinate, or 2HG include the accumulation of HIF-α and increased HIF target gene expression (235, 238), defects in collagen maturation (239), as well as hypermethylation and altered histone code due to disruption of epigenetic control of gene expression (236, 2…”
Background
Clinical and molecular genetics of patients with the Carney–Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD
Pasini, B., McWhinney, S. R., Bei, T. A., Matyakhina, L., Stergiopoulos, S. G., Muchow, M., Boikos, S. A., Ferrando, B., Pacák, K., Assié, G., et al. (2007) · European Journal of Human Genetics · doi:10.1038/sj.ejhg.5201904 · Cited by 483 · see citing works
Mitochondrial reactive oxygen species production in excitable cells: Modulators of mitochondrial and cell function
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“Hypoxia, increased succinate, and decreased aketoglutarate can each lead to inhibition of PH (208, 281), which permits translocation of HIF- to the nucleus to support HIF-–dependent transcription of the multitude of genes responsible for O2 transport, vascularization, and anaerobic energy production (208).”
Background
Metabolic checkpoints in activated T cells
Wang, R., & Green, D. R. (2012) · Nature Immunology · doi:10.1038/ni.2386 · Cited by 457 · see citing works
Regulation of angiogenesis by hypoxia-inducible factor 1
Hirota, K., & Semenza, G. L. (2006) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2005.12.003 · Cited by 466 · see citing works
Tumor glycolysis, an essential sweet tooth of tumor cells
Paul, S., Ghosh, S., & Kumar, S. (2022) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2022.09.007 · Cited by 449 · see citing works
Hypoxia-inducible factors: central regulators of the tumor phenotype
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“Similarly, inactivation of succinate dehydrogenase, which occurs in some renal, thyroid and colon cancers, leads to succinate accumulation and product inhibition of the PHDs [41]. www.sciencedirect.com Control of HIF-a translation The mammalian target of rapamycin (mTOR) kinase responds to nutrient and growth factor a…”
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Immunometabolism: Cellular Metabolism Turns Immune Regulator
Loftus, R. M., & Finlay, D. K. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.r115.693903 · Cited by 446 · see citing works
“Succinate can stabilize HIF1 by inhibiting the -ketoglutarate-dependent prolyl-hydroxylases responsible for tagging HIF1 for proteasomal degradation (27, 82, 83).”
A HIF1α Regulatory Loop Links Hypoxia and Mitochondrial Signals in Pheochromocytomas
Dahia, P. L. M., Ross, K. N., Wright, M. E., Hayashida, C. Y., Santagata, S., Barontini, M., Kung, A. L., Sanso, G., Powers, J. F., Tischler, A. S., et al. (2005) · PLoS Genetics · doi:10.1371/journal.pgen.0010008 · Cited by 443 · see citing works
“(D) Proposed model of HIF1α and SDHB interregulation. HIF1α downregulates SDHB, which leads to complex II dysfunction. High succinate levels resulting from loss of complex II, in turn, inhibit prolyl hydroxylase (PHD) activity [”
Background
Krebs cycle Reborn in macrophage immunometabolism
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“Importantly, inefficient SDH activity enabled succinate to accumulate to high levels and competitively inhibit PHDs, even in the absence of VHLmutations, an important oncogenic event in tumor formation (52).”
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A role for the NLRP3 inflammasome in metabolic diseases—did Warburg miss inflammation?
Wen, H., Ting, J. P. ‐., & O'Neill, L. A. J. (2012) · Nature Immunology · doi:10.1038/ni.2228 · Cited by 455 · see citing works
“This could lead to the buildup of intermediates such as succinate, a known inhibitor of PHD2, the enzyme that hydroxylates HIF-1α, leading to degradation of HIF-1&alpha”
SirT3 suppresses hypoxia inducible factor 1α and tumor growth by inhibiting mitochondrial ROS production
Bell, E. L., Emerling, B. M., Ricoult, S. J. H., & Guarente, L. (2011) · Oncogene · doi:10.1038/onc.2011.37 · Cited by 440 · see citing works
“In addition to pVHL, loss of succinate dehydrogenase, fumarate hydratase and REDD1 have been demonstrated to stabilize and activate HIF-1a in normoxic conditions, due to induction of ROS and mitochondrial metabolites (Isaacs et al., 2005; Selak et al., 2005; Guzy et al., 2008; Horak et al., 2010).”
Background
Oxygen availability and metabolic adaptations
Nakazawa, M. S., Keith, B., & Simon, M. C. (2016) · Nature reviews. Cancer · doi:10.1038/nrc.2016.84 · Cited by 431 · see citing works
Self-citation
Loss of the SdhB, but Not the SdhA, Subunit of Complex II Triggers Reactive Oxygen Species-Dependent Hypoxia-Inducible Factor Activation and Tumorigenesis
Guzy, R. D., Sharma, B., Bell, E., Chandel, N. S., & Schumacker, P. T. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.01338-07 · Cited by 427 · see citing works
“In a previous study, the suppression of SdhD expression led to an increase in HIF-1 stabilization, a response that was attributed to the inhibition of PHD by succinate that accumulated as a consequence of the impairment in complex II activity ( 43 ).”
BackgroundMethodInfluential
The transcription factor HIF-1α plays a critical role in the growth factor-dependent regulation of both aerobic and anaerobic glycolysis
Lum, J. J., Bui, T., Gruber, M., Gordan, J. D., DeBerardinis, R. J., Covello, K. L., Simon, M. C., & Thompson, C. B. (2007) · Genes & Development · doi:10.1101/gad.1529107 · Cited by 429 · see citing works
“In certain tumors, high levels of HIF-1 are observed in well-oxygenated environments and deficiencies in the mitochondrial enzymes, succinate dehydrogenase and fumarase, have been associated with stabilization of HIF-1 under normoxic conditions (Isaacs et al. 2005; Selak et al. 2005).”
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Role and regulation of prolyl hydroxylase domain proteins
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Anticancer Targets in the Glycolytic Metabolism of Tumors: A Comprehensive Review
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“Mutations in enzymes coupling the TCA cycle to OXPHOS have been identified (Pollard et al., 2003; Selak et al., 2005; Dang et al., 2009) but account only marginally for the total population of cell lines performing aerobic glycolysis.”
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Altered metabolite levels in cancer: implications for tumour biology and cancer therapy
Sullivan, L. B., Gui, D. Y., & Heiden, M. G. V. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2016.85 · Cited by 406 · see citing works
Oncometabolites: linking altered metabolism with cancer
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“In SDH-and FH-deficient cells and tumors, the activation of a HIF-orchestrated “pseudohypoxic” response has been reported (41–44), which could at least in part be attributed to the allosteric inhibition of HIF prolyl hydroxylases (PHDs) by elevated levels of succinate or fumarate (Figure 2).”
Targeting cancer vulnerabilities with high-dose vitamin C
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miR-210 is overexpressed in late stages of lung cancer and mediates mitochondrial alterations associated with modulation of HIF-1 activity
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Multiple Biological Activities of Lactic Acid in Cancer: Influences on Tumor Growth,Angiogenesis and Metastasis
Dhup, S., Dadhich, R. K., Porporato, P. E., & Sonveaux, P. (2012) · Current Pharmaceutical Design · doi:10.2174/138161212799504902 · Cited by 419 · see citing works
“Their conclusion that molecular features mimicking those of 2-oxoglutarate are necessary for the biological activity has now been challenged by others having shown that succinate (a product of the PHD reaction), fumarate, (iso)citrate and 2-hydroxyglutarate (substituting the 2-oxo group by a 2hydroxyl group) are also…”
Background
Mitochondria as a Source of Reactive Oxygen and Nitrogen Species: From Molecular Mechanisms to Human Health
Figueira, T. R., de Barros, M. H., Camargo, A. A., Castilho, R. F., Ferreira, J. C. B., Kowaltowski, A. J., Sluse, F. E., de Souza-Pinto, N. C., & Vercesi, A. E. (2012) · Antioxidants and Redox Signaling · doi:10.1089/ars.2012.4729 · Cited by 417 · see citing works
Personalized Management of Pheochromocytoma and Paraganglioma
Nölting, S., Bechmann, N., Taïeb, D., Beuschlein, F., Faßnacht, M., Kroiß, M., Eisenhofer, G., Grossman, A. B., & Pacák, K. (2021) · Endocrine Reviews · doi:10.1210/endrev/bnab019 · Cited by 441 · see citing works
“This causes HIF-α stabilization, mitochondrial DNA impairment, collagen instability, and most likely an abnormal immune microenvironment (45-48).”
Background

Abstract IA-17: The roles of prolyl hydroxylases in metabolism and cancer
Gottlieb, E. (2009) · Cancer Research · doi:10.1158/0008-5472.fbcr09-ia-17
Self-citation
Overcoming the Loss of Mitochondrial Tumor Suppressors by Reactivating HIF Prolyl Hydroxylases
Gottlieb, E. (2007) · Molecular Cancer Therapeutics
Self-citation
Mitochondrial succinate is instrumental for HIF1α nuclear translocation in SDHA-mutant fibroblasts under normoxic conditions
Brière, J.-J., Favier, J., Bénit, P., Ghouzzi, V. E., Lorenzato, A., Rabier, D., Renzo, M. F. D., Gimenez‐Roqueplo, A., & Rustin, P. (2005) · Human Molecular Genetics · doi:10.1093/hmg/ddi359 · Cited by 153 · see citing works
Le cycle de Krebs dans la pathologie humaine : succinate désydrogénase et tumorigenèse
Brière, J.-J. (2006)
Accumulation of Krebs cycle intermediates and over-expression of HIF1α in tumours which result from germline FH and SDH mutations
Pollard, P. J., Brière, J. J., Alam, N. A., Barwell, J., Barclay, E., Wortham, N. C., Hunt, T., Mitchell, M., Olpin, S., Moat, S. J., et al. (2005) · Human Molecular Genetics · doi:10.1093/hmg/ddi227 · Cited by 865 · see citing works

Authors: Selak, M. A., Armour, S. M., MacKenzie, E. D., Boulahbel, H., Watson, D. G., Mansfield, K. D., Pan, Y., Simon, M. C., Thompson, C. B., & Gottlieb, E.
Affiliations: Cancer Research UK (GB)
University of Pennsylvania (US)
University of Strathclyde (GB)
Corresponding author: Gottlieb, Eyal
ORCID: Selak, Mary A.
Armour, Sean M.
Watson, David G.
Mansfield, Kyle D.
Simon, M.Celeste
Thompson, Craig B.
Gottlieb, Eyal
Venue: Cancer Cell
Publisher: Elsevier BV
Published: 2005-01
Volume: 7
Issue: 1
Pages: 77-85
ISSN: 1535-6108 (ISSN-L)
DOI: 10.1016/j.ccr.2004.11.022
OpenAlex: W2057199368
Cited by: 2,108
References: 47
Citations by year: 2026: 110 · 2025: 115 · 2024: 97 · 2023: 97 · 2022: 116 · 2021: 139 · 2020: 128 · 2019: 123 · 2018: 93 · 2017: 107 · 2016: 110 · 2015: 107 · 2014: 108 · 2013: 109 · 2012: 86
FWCI: 26.39
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 3119 d)
Locations: Cancer Cell (publishedVersion)
PubMed (publishedVersion)
Strathprints: The University of Strathclyde institutional repository (University of Strathclyde) (acceptedVersion)
ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
Funders: Beatson Institute for Cancer Research
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Health Sciences › Medicine › Oncology › Ear and Head Tumors
Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Ferroptosis and cancer prognosis
Keywords: succinic acid, succinate dehydrogenase, HIF-1α, prolyl hydroxylase, mitochondrial dysfunction, tumor suppressor proteins, carcinogenesis, VHL, tumor angiogenesis, fumarate hydratase
MeSH terms: Animals, Cell Line, Cell Transformation, Neoplastic, Citric Acid Cycle, Enzyme Activation, Humans, Mitochondria, Oncogenes, Procollagen-Proline Dioxygenase, Succinate Dehydrogenase, Transcription Factors, Signal Transduction, Gene Expression Regulation, Enzymologic, Reactive Oxygen Species, Succinic Acid, Tumor Suppressor Proteins, RNA, Small Interfering, Ubiquitin-Protein Ligases, Von Hippel-Lindau Tumor Suppressor Protein, Hypoxia-Inducible Factor 1, alpha Subunit

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

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