The DOI matches its Crossref record; 45 of the 47 references it cites were found in a registry or an index; 1 of the 7 sources its claims cite were checked for support.
Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-α prolyl hydroxylase
Open accessAbstract
Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-α prolyl hydroxylase
Overview
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
Cites
Statistics
Verification
Claims the paper makes
16 Own result · 3 No full text of the sources · 3 Own interpretation · 1 Supported so far · 1 Own method · 1 No basis given
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Since pVHL binding to the ODD domain is dependent on PHD activity (Kaelin, 2002;Safran and Kaelin, 2003)”
§ Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-␣ prolyl hydroxylase > Elevation of succinate level following downregulation of SDH leads to PHD inhibition and HIF-1␣ stabilization in cells
What the sources say
- Not checked — no full text of the sourcecites Kaelin, 2002 source
- Supportedcites Safran and Kaelin, 2003 source
The section “Prolyl hydroxylation earmarks HIF for destruction” (p. 2) says pVHL binds HIF1α only after prolyl residues in its ODD are enzymatically hydroxylated, and identifies PHD proteins as the hydroxylases. The Figure 1 discussion (p. 3) adds that when PHD cannot hydroxylate HIF, pVHL does not recognize it. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“succinate, which accumulates as a result of SDH inhibition, inhibits HIF-␣ prolyl hydroxylases in the cytosol”
§ Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-␣ prolyl hydroxylase > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“cells incubated with 20 mM DMS for 48 hr showed elevated levels of HIF-1␣ under normoxic conditions (Figure 5B).”
§ Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-␣ prolyl hydroxylase > Elevation of succinate level following downregulation of SDH leads to PHD inhibition and HIF-1␣ stabilization in cells
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-␣ prolyl hydroxylase > Reactive oxygen species do not play a role in HIF-1␣ induction after SDH inhibition
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Reactive oxygen species do not play a role in HIF-1␣ induction after SDH inhibition · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-␣ prolyl hydroxylase > Elevation of succinate level following downregulation of SDH leads to PHD inhibition and HIF-1␣ stabilization in cells
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In this paper, we show that downregulation of SDH activity results in the accumulation of succinate in cells”
§ Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-␣ prolyl hydroxylase > Introduction
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“a clear accumulation of HIF-1␣ in the nuclei of cells treated with DMS was observed (Figure 5C)”
§ Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-␣ prolyl hydroxylase > Elevation of succinate level following downregulation of SDH leads to PHD inhibition and HIF-1␣ stabilization in cells
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“no significant difference was observed in the redox state of SDH-inhibited cells as compared to the control scRNAi-transfected cells (Table 1).”
§ Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-␣ prolyl hydroxylase > Reactive oxygen species do not play a role in HIF-1␣ induction after SDH inhibition
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-␣ prolyl hydroxylase > Reactive oxygen species do not play a role in HIF-1␣ induction after SDH inhibition
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“succinate, which accumulates as a result of SDH inhibition, inhibits HIF-␣ prolyl hydroxylases in the cytosol”
§ Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-␣ prolyl hydroxylase > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- 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.
- It may state two separate claims as one. 3
- The quote only partly states this claim. 1
- Probably not a substantial claim. 2
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The IC 50 was 5.0ف mM for succinate under these reaction conditions, a level that is attainable in SDH-inhibited cells (Table 1).”
§ Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-␣ prolyl hydroxylase > Succinate is accumulated in SDH-inhibited cells
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“leading to stabilization and activation of HIF-1␣.”
§ Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-␣ prolyl hydroxylase > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The quote only partly states this 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.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“succinate has been shown to inhibit some ␣-ketoglutarate-dependent oxygenases, including procollagen prolyl hydroxylase and thymine-7-hydroxylase (Holme, 1975;Myllyla et al., 1977).”
§ Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-␣ prolyl hydroxylase > Introduction
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Actin was used as loading control.”
§ Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-␣ prolyl hydroxylase > Experimental procedures Succinic acid quantification by GCMS Plasmids
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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).”
§ Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-␣ prolyl hydroxylase > Introduction
What the sources say
- Not checked — no full text of the sourcecites Schofield and Zhang, 1999 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“the PHDs utilize ␣-ketoglutarate as a cosubstrate and require ferrous iron (Fe 2ϩ ) and ascorbate as cofactors (Kaelin, 2002;Schofield and Zhang, 1999).”
§ Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-␣ prolyl hydroxylase > Introduction
What the sources say
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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.”
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Experimental — accuracy not yet measuredIn the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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
In the citing paper
“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]
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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]
In the citing paper
“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.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-␣ prolyl hydroxylase > Elevation of succinate level following downregulation of SDH leads to PHD inhibition and HIF-1␣ stabilization in cells
“without pVHL (i, iii, v) or with pVHL (ii, iv, vi) together with one of the indicated siRNA constructs: scRNAi (i-iv), Di3 (v), or Di4 (vi).”
§ Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-␣ prolyl hydroxylase > Elevation of succinate level following downregulation of SDH leads to PHD inhibition and HIF-1␣ stabilization in cells
“When cells were cotransfected with GFP-ODD, HA-tagged pVHL, and Therefore, it is likely that in SDH-inhibited cells, the HIF-1␣ ODD domain is hydroxylated less efficiently, and consequently the either of the siRNA constructs, higher GFP levels were observed in Di3-and Di4-transfected cells compared to scRNAi-trans-binding of pVHL to GFP-ODD is reduced.”
Citations
Cites
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×
“In particular, elevated levels al., 2001; Jaakkola et al., 2001; Yu et al., 2001).”
BackgroundHIFα Targeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for O 2 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×
“, 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).”
BackgroundEpstein, 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×
“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×
“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×
“) and ascorbate as cofactors (Kaelin, 2002; Scho-field and Zhang, 1999).”
BackgroundMethodInfluentialA 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×
“The tumor suppressor p53, which is known to elevate ROS production (Polyak et al., 1997), was used as a positive control.”
MethodOxygen sensing by HIF hydroxylases
Schofield, C. J., & Ratcliffe, P. J. (2004) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1366 · Cited by 2,068
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×
“…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).”
BackgroundAsparagine 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×
“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).”
BackgroundLando, 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
Research works printed but not linked: 1
- Beasley, 2002, Hypoxia-inducible factors HIF-1α and HIF-2α in head and neck cancer, Cancer Res., 62, 2493
Cited by
Sorted by citations
Items 1,701–1,800 of 2,106
Glutamine-dependent effects of nitric oxide on cancer cells subjected to hypoxia-reoxygenation
Xing, D., Benavides, G. A., Johnson, M. S., Tian, R., Barnes, S., & Darley-Usmar, V. M. (2022) · Nitric Oxide · doi:10.1016/j.niox.2022.11.003 · Cited by 3
Glucose deprivation impairs hypoxia-inducible factor-1α synthesis
Hubert, M., Stuart, S. E., & Ohh, M. (2024) · Discover Oncology · doi:10.1007/s12672-024-01484-1 · Cited by 3
Succinate aggravates NAFLD progression to liver cancer on the onset of obesity: Anin silicomodel
Ray, I., Dasgupta, A., & De, R. K. (2018) · Journal of Bioinformatics and Computational Biology · doi:10.1142/s0219720018500087 · Cited by 3
HIFα as a target for different oncoproteins during carcinogenesis
Kobliakov, V. A. (2019) · Advances in molecular oncology · doi:10.17650/2313-805x-2018-5-4-64-71 · Cited by 3
Regulating Mitochondrial Respiration in Cancer
Serafim, T. L., & Oliveira, P. J. (2014) · Cancer drug discovery and develogment/Cancer drug discovery and development · doi:10.1007/978-1-4614-9545-1_3 · Cited by 3
“In several tumors, impairment of the TCA cycle leads to succinate accumulation, which acts as a signaling molecule and triggers the reactivation of HIF-1 [269].”
BackgroundPaddenberg, R., Howold, N., Hoger, C., Janßen, H., Grau, V., & Kummer, W. (2009) · Cell Biochemistry and Function · doi:10.1002/cbf.1608 · Cited by 3
A Ramble through the Cell: How Can We Clear Such a Complicated Trail?
Bobich, J. A. (2006) · CBE—Life Sciences Education · doi:10.1187/cbe.05-12-0138 · Cited by 3
“As examples, who could have correctly guessed in advance that succinate dehydrogenase would be a tumor suppressor (Selak et al., 2005) or that the proteasome is involved in the regulation of gene expression (Lee et al., 2005)?”
BackgroundMolecular Pathology of the Genitourinary Tract: Molecular Pathology of Kidney and Testes
Sirintrapun, S. J., & Parwani, A. V. (2009) · Surgical pathology clinics · doi:10.1016/j.path.2008.08.003 · Cited by 3
Adult Head and Neck Sarcomas: Rare Localization with Difficult Therapeutic Management
Oualla, K. (2013) · Journal of Cancer Science & Therapy · doi:10.4172/1948-5956.1000248 · Cited by 3
Pathologies liées aux déficits du cycle de Krebs
Bénit, P., Bortoli, S., Chrétien, D., Rak, M., & Rustin, P. (2018) · Revue Francophone des Laboratoires · doi:10.1016/s1773-035x(18)30120-5 · Cited by 3
“[8] Selak MA, Armour SM, MacKenzie ED, et al.”
BackgroundOhtake, M., Tateishi, K., Murata, H., Nagashima, Y., Yamanaka, S., & Yamamoto, T. (2018) · World Neurosurgery · doi:10.1016/j.wneu.2018.02.147 · Cited by 3
Обрезан, А. Г., & Щербакова, Н. В. (2020) · Kardiologiia · doi:10.18087/cardio.2020.2.n985 · Cited by 3
Pheochromocytoma and Paraganglioma
Robledo, M., Currás, M., & Cascón, A. (2021) · Springer eBooks · doi:10.1007/978-3-030-74448-9_5 · Cited by 3
Varshavi, D., Varshavi, D., McCarthy, N., Veselkov, K., Keun, H. C., & Everett, J. R. (2021) · Metabolomics · doi:10.1007/s11306-021-01852-w · Cited by 3
“One of the consequences of this inhibition is the stabilization of the transcription factor hypoxia-inducible factor 1-alpha (HIF-1α) and the generation of a pseudo-hypoxic response reducing oxidative phosphorylation and promoting glycolysis (Selak et al. 2005; Tavares et al., 2015).”
BackgroundCell Signaling and Transcription
Rehmani, I., Liu, F., & Liu, A. (2013) · Wiley eBooks · doi:10.1002/9781118355886.ch8 · Cited by 5
D’Alessandro, A., Nozik‐Grayck, E., & Stenmark, K. R. (2017) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201706-1065ed · Cited by 3
“Tannahill GM, Curtis AM, Adamik J, Palsson-McDermott EM, McGettrick AF, Goel G, Frezza C, Bernard NJ, Kelly B, Foley NH, Zheng L, Gardet A, Tong Z, Jany SS, Corr SC, Haneklaus M, Caffrey BE, Pierce K, Walmsley S, Beasley FC, Cummins E, Nizet V, Whyte M, Taylor CT, Lin H, Masters SL, Gottlieb E, Kelly VP, Clish C, Auro…”
BackgroundInfluentialTranscription | Regulation of Gene Transcription by Hypoxia-Inducible Factor 1α
Child, F., Frost, J., Shakir, D., Wilson, J. W., & Rocha, S. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-819460-7.00033-5 · Cited by 4
Metabolic permissiveness: how tissue context shapes cancerPreprint
Moschandrea, C., & Frezza, C. (2026) · Genes & Development · doi:10.1101/gad.353516.125 · Cited by 4
“…another onco-metabolite that competitively inhibits α KGDs, such as prolyl hydroxylases (PHDs), thereby stabilizing HIF-1 α and promoting a pseudohypoxic transcriptional program (Baysal et al. 2000; Gottlieb and Tomlinson 2005; Pollard et al. 2005, 2006; Selak et al. 2005; Bardella et al. 2011b).”
HIF inhibition: Current strategies and clinical challenges
Więch-Walów, A., Bartoszewska, S., Barton, A., Czechowicz, P., Dudzik, J., Wielockx, B., Collawn, J. F., & Bartoszewski, R. (2026) · Redox biology · doi:10.1016/j.redox.2026.104220 · Cited by 3
“Accordingly, accumulation of tricarboxylic-acid-cycle intermediates such as succinate and fumarate, most often due to SDH or FH loss-of-function, competitively inhibits PHDs and stabilizes HIF-α during normoxia [169,170].”
Chikungunya Virus, Metabolism, and Circadian Rhythmicity Interplay in Phagocytic Cells
Alvarez-García, L., Sánchez‐García, F. J., Vázquez-Pichardo, M., & Moreno‐Altamirano, M. M. B. (2023) · Metabolites · doi:10.3390/metabo13111143 · Cited by 3
Semzenisi, E., Hodor, D., Sall, I. M., Toma, C. G., & Tăbăran, F. (2024) · Frontiers in Veterinary Science · doi:10.3389/fvets.2024.1409701 · Cited by 2
Weber, C. M., Moiz, B., Kheradmand, M., Scott, A., Kettula, C., Wunderler, B., Vargas, V. A., & Clyne, A. M. (2025) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x241310729 · Cited by 2
Ruiz, J. D. C., Sánchez, J. I. A., Fernández, J. J. D., Díaz‐Brochero, C., & Martínez, L. (2025) · Experimental Physiology · doi:10.1113/ep092109 · Cited by 3
Metabolic Effects of the Cancer Metastasis Modulator MEMO1
Ghanbarian, M., Dolgova, N. V., Vizeacoumar, F. S., Vizeacoumar, F. J., Michel, D. L., El‐Aneed, A., & Dmitriev, O. Y. (2025) · Metabolites · doi:10.3390/metabo15040277 · Cited by 2
“It also acts as a ligand for SUCNR1 in cancer cells, activating the AKT/mTOR/HIF-1 α signaling axis and further promoting tumor progression [73].”
Wang, T., Gong, B., Shi, K., Hu, G., Sun, L., & Xu, Y. (2025) · Clinica Chimica Acta · doi:10.1016/j.cca.2025.120702 · Cited by 3
Wang, R., & Yan, Z. (2025) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2025.1671115 · Cited by 2
Prokaryotic organelle mitochondria drive tumorigenesis: “the original sin”
Wang, C., Luo, M., Zhou, J., Zhang, Q., Xiawei, J., He, J., Wang, L., Huang, Y., Xu, X., & 王方岩 (2026) · Frontiers in Oncology · doi:10.3389/fonc.2025.1632702 · Cited by 3
“In the cytoplasm, the inhibition of PHDs by tumor metabolites activates and stabilizes HIF-1 a (87).”
Jia, A., Zhang, X., Zhou, J., Ma, Y., Wang, J., Gong, Y., Song, W., Hu, H., Yu, Y., Yang, H., et al. (2026) · Cell Metabolism · doi:10.1016/j.cmet.2026.01.001 · Cited by 4
Surti, M., Gupta, A., Janiyani, K., Adnan, M., & Patel, M. B. (2026) · Journal of the National Cancer Center · doi:10.1016/j.jncc.2026.01.009 · Cited by 2
“88 , 110–112 However, such mutations appear to be relatively rare in human ovarian and peritoneal tumors, 113 and emerging evidence suggests that some tumors retain active mitochondrial function with intact OXPHOS.”
Malatesta, S., Benedetti, V. V., Salviati, E., Illi, B., Manni, I., Middonti, E., Vinciguerra, G. L. R., Licursi, V., Troilo, F., Colotti, G., et al. (2026) · Cell Death and Disease · doi:10.1038/s41419-026-08475-w · Cited by 2
Li, Y., Liu, S. Q., Chu, C., & Yang, J. (2026) · iScience · doi:10.1016/j.isci.2026.115217 · Cited by 3
“84 Increased HIF-1 α signaling stimulates SMC proliferation by inducing the expression of growth factors and promoting mitochondrial fission, thereby supporting the metabolic and structural demands of SMC expansion.”
Vascular changes and their implications in lipedema
Al-Ghadban, S., Guo, Y., Juśkiewicz, Z. J., Crescenzi, R. L., Li, X., Isakson, B. E., & Hollenbeck, S. T. (2026) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2026.1819443 · Cited by 2
“Under hypoxic and inflammatory stress, disruption of mitochondrial oxidative metabolism leads to succinate accumulation, which functions as a key metabolic signal (Selak et al., 2005; Wojtovich et al., 2013).”
Mechanisms Involved in Pathological Succinate-Mediated Signaling
Bernabe-Yepes, B., & Zazueta, C. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27104328 · Cited by 2
“Notably, HIF-1 α enhances the production of IL-1 β in macrophages [27,28].”
A mechanistic computational model of the HIF signaling pathway in endothelial cells
Oliveira, R. H. D. M., Pathak, A. P., & Popel, A. S. (2026) · iScience · doi:10.1016/j.isci.2026.116195 · Cited by 2
“64 In such settings, our model would be expected to underestimate HIF stabilization, and incorporating these additional regulators is noted as a direction for future development.”
Looking Back to the Future of Mitochondrial Research
Bernardi, P. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.682467 · Cited by 3
“The discovery that mitochondria are involved in the HIFmediated response to hypoxia (Samanta and Semenza, 2018) through succinate-dependent stabilization of HIF-1α (Selak et al., 2005) and modulation of expression of cytochrome oxidase subunits (Fukuda et al., 2007) was a turning point for our understanding of metabol…”
BackgroundŁoń, I., Kunikowska, J., Jędrusik, P., et al. (2021) · Intractable & Rare Diseases Research · doi:10.5582/irdr.2021.01047 · Cited by 2
“Molecular data showed that mutations in the genes coding for SDH subunits result in accumulation of succinate and inhibition of HIF-1 hydroxylases leading to stabilization of HIF1 (28,29).”
BackgroundRole of succinate dehydrogenase in hepatocellular carcinoma
Srivani, G., Imran, M., Merchant, N., Mandala, J. P., & Nagaraju, G. P. (2022) · Elsevier eBooks · doi:10.1016/b978-0-323-98806-3.00014-3 · Cited by 2
The Intersection of Pulmonary Vascular Disease and Hypoxia-Inducible Factors
Suresh, M. V., Aggarwal, V., & Raghavendran, K. (2023) · Interventional Cardiology Clinics · doi:10.1016/j.iccl.2023.03.010 · Cited by 3
A big picture of the mitochondria-mediated signals: From mitochondria to organism
Acar, N. V., & Özgül, R. K. (2023) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2023.08.032 · Cited by 2
Congenital Cyanotic Heart Disease and the Association with Pheochromocytomas and Paragangliomas
Jones, R. B., & Cohen, D. L. (2023) · Current Cardiology Reports · doi:10.1007/s11886-023-01974-8 · Cited by 3
Saeed, A., Ejaz, S. A., Aziz, M., et al. (2023) · Química Nova · doi:10.21577/0100-4042.20230131 · Cited by 2
Rodríguez, S., Rodríguez-Jaime, M. F., & León-Prieto, C. (2024) · Critical Reviews in Physical and Rehabilitation Medicine · doi:10.1615/critrevphysrehabilmed.2024052624 · Cited by 2
Alsawaf, Y., Maksimovic, I., Zheng, J., Zhang, S., Vučković, I., Dzeja, P. P., Macura, S. I., & Irazabal, M. V. (2024) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00131.2024 · Cited by 3
Gastrointestinal Malignancy: Genetic Implications to Clinical Applications
Trembath, H. E., Yeh, J. J., & Lopez, N. (2024) · Cancer treatment and research · doi:10.1007/978-3-031-61238-1_15 · Cited by 3
He, X., Geng, Z., Zou, G., Cui, Z., Wang, Y., Song, J., Zhang, J., Shao, Y., Feng, J., Wu, Y., et al. (2024) · Stem Cells and Development · doi:10.1089/scd.2024.0160 · Cited by 2
“48 Increased succinic acid can also be available for heme synthesis, which may, in turn, affect Hb production.”
SDHA: a key player in T cell-mediated intestinal disease severity
Izquierdo, J. M. (2022) · Cellular and Molecular Immunology · doi:10.1038/s41423-021-00820-7 · Cited by 2
Hanse, E. A., & Kong, M. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.962928 · Cited by 2
Cancer Hypoxia and the Tumour Microenvironment as Effectors of Cancer Metabolism
Armitage, E. G., Kotze, H. L., & Williams, K. J. (2014) · SpringerBriefs in systems biology · doi:10.1007/978-1-4939-0615-4_2 · Cited by 2
“Mutations in succinate dehydrogenase (SDH) and fumarate hydratase (FH) lead to increased levels of succinate and fumarate, respectively, which inhibit activity of the HIF–PHD enzymes, resulting in stabilisation in “aerobic” conditions (Isaacs et al. 2005; Pollard et al. 2005; Selak et al. 2005).”
BackgroundExtraadrenal pheochromocytoma associated to SDHD gene mutation
Lendvai, N., Szabó, I., Butz, H., Bekő, G., Horányi, J., Tarjányi, M., Alföldi, S., Szabó, I., Rácz, K., & Patócs, A. (2009) · Orvosi Hetilap · doi:10.1556/oh.2009.28587 · Cited by 2
Sánchez, F. S. L., Lozano, M. N., Gorjón, P. S., Medina, A., Herrera, Á. M. M., & González‐Sarmiento, R. (2010) · Angiología · doi:10.1016/s0003-3170(10)70051-1 · Cited by 2
Imagerie moléculaire nucléaire des paragangliomes
Taïeb, D., Tessonnier, L., & MUNDLER, O. (2010) · Médecine Nucléaire · doi:10.1016/j.mednuc.2010.06.009 · Cited by 2
Park, H. (2008) · Toxicological Research · doi:10.5487/tr.2008.24.2.101 · Cited by 2
“Inherited genetic defects in either fumarate hydratase (Selak et al., 2005) or succinate dehydroge- nase (Pollard et al., 2005) cause tumor, however the mechanism of this cancer syndrome has not been known.”
BackgroundDysfunction of Mitochondrial ATP Production As a Target for Personalized Cancer Therapy
Tsuneoka, M., Teye, K., Okamoto, K., & Tanaka, Y. (2009) · Current pharmacogenomics and personalized medicine (Online)/Current pharmacogenomics and personalized medicine · doi:10.2174/187569209787582358 · Cited by 2
Genetic Diagnosis of Pheochromocytoma
Takekoshi, K., Isobe, K., & Kawakami, Y. (2008) · Nihon Naika Gakkai Zasshi · doi:10.2169/naika.97.2558 · Cited by 2
The Electron Transport Chain and Carcinogenesis
Brière, J.-J., Bénit, P., & Rustin, P. (2008) · Humana Press eBooks · doi:10.1007/978-1-59745-435-3_2 · Cited by 2
“2) [35, 36].”
Tena, I., Ponce, J. L., Tajahuerce, M., Vercher-Conejero, J. L., Cifrián, M., Wolf, K. I., Miret, M., Olmo-García, M. I. D., Reboll, R., Conde-Moreno, A. J., et al. (2017) · Journal of Clinical and Translational Endocrinology Case Reports · doi:10.1016/j.jecr.2017.12.001 · Cited by 2
Paraganglioma and Pheochromocytoma
Iacobone, M., & Torresan, F. (2021) · Springer eBooks · doi:10.1007/978-3-030-62241-1_15 · Cited by 2
Li, Z., Chai, Y., Zhou, Z., et al. (2021) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2021.10066 · Cited by 2
“The downregulated hsa_circRNA_103546 is able to indirectly regulate the low expression of SDHD. Selak et al (37) reported that the accumulation of succinate due to SDH inhibition led to activation of HIF‑1α, which may also be involved in the patho‑ genesis of IH.”
BackgroundRepair of retrohepatic inferior vena cava injury.
Chaudhry, A. K., Azam, M., & Maqsood, R. (2003) · PubMed · Cited by 2
Raimundo, N., Fernández-Mosquera, L., & Yambire, K. F. (2016) · Springer eBooks · doi:10.1007/978-1-4939-3612-0_9 · Cited by 4
Mitochondria as Targets for Cancer Therapy
Ralph, S. J., & Neužil, J. (2008) · Springer eBooks · doi:10.1007/978-0-387-84835-8_12 · Cited by 2
Oxidative Stress and Hypoxia in Cancer: Implications for Radiation Therapy
Roy, A., Tubin, S., Dwarakanath, B. S. R., & Gupta, S. (2022) · Springer eBooks · doi:10.1007/978-981-15-9411-3_136 · Cited by 3
Molecular Basis of Response to Hypoxia
Krishnan, A., & Ansari, H. K. (2023) · Springer eBooks · doi:10.1007/978-981-99-7652-2_2 · Cited by 2
Molecular Biology of Pheochromocytomas and Paragangliomas
King, E. E., & Dahia, P. L. M. (2009) · Springer eBooks · doi:10.1007/978-1-4419-1069-1_13 · Cited by 2
Weihe, E. (2009) · State and University Library Bremen · Cited by 2
Hypoxia in the Pathogenesis of Retinal Disease
Poulaki, V. (2007) · Springer eBooks · doi:10.1007/978-3-540-29542-6_7 · Cited by 2
The Signaling Nature of Cellular Metabolism: The Hypoxia Signaling
Fábián, Z. (2019) · IntechOpen eBooks · doi:10.5772/intechopen.79952 · Cited by 3
Nanotoxicity, Cytotoxicity, and Genotoxicity Mechanisms of Nanomaterials
Madkour, L. H. (2020) · Nanomedicine and nanotoxicology · doi:10.1007/978-3-030-37297-2_2 · Cited by 3
MOLECULAR AND CLINICAL CHARACTERISTICS OF TRICARBOXYLIC ACID CYCLE-ASSOCIATED TUMORS
Lehtonen, H. J. (2008) · Työväentutkimus Vuosikirja · Cited by 2
The Role Of Fumarase (FH) In Tumorigenesis
Lehtonen, R. (2006) · Työväentutkimus Vuosikirja · Cited by 2
Loss of SDHB reprograms energy metabolisms and inhibits high fat diet induced metabolic syndromesPreprint
Mu, C., Ma, B., Zhang, C., Geng, G., Zhang, X., Chen, L., Wang, M., Li, J., Zhao, T., Cheng, H., et al. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/259226 · Cited by 3
“succinate-PHD-HIF1A axis [21] may contribute to these processes.”
BackgroundAltered MAM function shifts mitochondrial metabolism in SOD1-mutant models of ALSPreprint
Larrea, D., Tamucci, K. A., Kabra, K., VELASCO, K. R., Yun, T. D., Pera, M., Montesinos, J., Agrawal, R. R., Smerdon, J. W., Lowry, E. R., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.09.22.508778 · Cited by 2
“…induce the expression of hypoxia-inducing factor 1α (HIF1α) (Kaewpila et al., 2008), could help explain the development of pseudo-hypoxic phenotypes (Selak et al., 2005) in the disease and the increased expression of HIF1α target genes frequently observed in ALS models (Sato et al., 2012, 2013).”
BackgroundValine Catabolism Drives Bioenergetic and Lipogenic Fuel Plasticity in Prostate CancerPreprint
Bidgood, C. L., Philp, L., Rockstroh, A., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.01.01.573829 · Cited by 2
“Succinate has been identified as having many pro-oncogenic roles, including HIF1α stabilisation 35,36 , alteration of the tumour microenvironment 40 , promotion of metastatic potential via enhanced EMT 37 , suppression of anti-392 tumour immune responses 41,42 and the activation of pro-inflammatory…”
BackgroundStewart, A. E., Zachman, D. K., Castellano‐Escuder, P., Kelly, L. M., Zolyomi, B., Aiduk, M. D. I., Delaney, C. D., Lock, I. C., Bosc, C., Bradley, J., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.02.26.640463 · Cited by 2
The 3PAs syndrome and succinate dehydrogenase deficiency in pituitary tumors
Xekouki, P., Daraki, V. N., Betsi, G., Chrysoulaki, M., Sfakiotaki, M., Mytilinaiou, M. G., & Stratakis, C. A. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-814537-1.00001-4 · Cited by 1
Reductive carboxylation of glutamine as a potential target in acute myeloid leukemia
Roma, A., Goodridge, L. D., & Spagnuolo, P. A. (2023) · Oncotarget · doi:10.18632/oncotarget.28474 · Cited by 1
Identification of the binding proteins of organic acid metabolites by matrix thermal shift assay
Li, K., Ye, Y., Zhang, X., Zhou, J., Li, Y.-N., & Ye, M. (2024) · Chinese Journal of Chromatography · doi:10.3724/sp.j.1123.2023.07002 · Cited by 1
A Mathematical Exploration of SDH-b Loss in Chromaffin Cells
Vera-Sigüenza, E., Rana, H., Nashebi, R., Cloete, I., Kl’uvčková, K., Spill, F., & Tennant, D. A. (2025) · Bulletin of Mathematical Biology · doi:10.1007/s11538-025-01427-z · Cited by 2
“These are rare tumours of the peripheral nervous system and adrenal glands, respectively (Goncalves et al. 2021; Li and Ye 2014; Letouzé et al. 2013; Selak et al. 2005; Brière et al. 2005).”
Damage-associated molecular patterns as metabolic regulators of innate immunity
Ryan, T. A. J., Zanoni, I., & Gioia, M. D. (2025) · Elsevier eBooks · doi:10.1016/b978-0-443-15447-8.00007-6 · Cited by 2
Succinate reduces biological activity and mitochondrial function of human adipose-derived stem cells
Wang, B., Wang, X., Guo, M., & Xu, H. (2025) · Cell Cycle · doi:10.1080/15384101.2025.2508109 · Cited by 2
“However, excess succinate can be transported to the cytosol via the dicarboxylic acid translocator and the voltage-dependent anion channel located in the mitochondrial membrane [5].”
Targeting Metabolic Reprogramming: A New Frontier in Cancer Therapy
Thakur, R. K., & Kumari, N. (2025) · Springer eBooks · doi:10.1007/978-981-96-7336-0_9 · Cited by 1
Coste, A., Buffet, A., Duboeuf, M., Boudif, S., Grassot, L., Ouelaa, B., Sueur, A., Lounis, T., Pérol, O., Fervers, B., et al. (2025) · Scientific Reports · doi:10.1038/s41598-025-09166-w · Cited by 1
“…(1) DNA and histone demethylases responsible for genome hypermethylation and consequently the activation of carcinogenesis by the repression of TSG; and (2) HIF-prolyl hydroxylases responsible for the inappropriate activation of angiogenesis pathways in normoxia, known as “pseudohypoxia” 9,10 .”
First Family with SDHC-Associated Mediastinal Paragangliomas in the Czech Republic
Hamplová, B., Musil, Z., Zelinka, T., et al. (2025) · Bratislavské lekárske listy/Bratislava medical journal · doi:10.1007/s44411-025-00277-4 · Cited by 1
“Loss-of-function mutations in SDHC lead to accumulation of succinate, which acts as an oncometabolite and drives tumorigenesis through inhibition of α-ketoglutarate-dependent dioxygenases and stabilization of hypoxia-inducible factors [12].”
Exploiting metabolic vulnerabilities to improve cancer therapeutics
Ibrahim, I. H., Lin, C.-H., Zhou, M., Yang, J., Sobol, R. W., & Tan, M. (2025) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2025.08.002 · Cited by 2
Liu, S., Lv, J., Peng, P., Song, X., Dai, P., Liu, F., Yao, Y., Zhu, C., & Lin, C. (2025) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2025.120646 · Cited by 1
Yang, L., Liu, Q., Su, J., Jiang, L., Li, Z., & Peng, H. (2025) · Cancer Cell International · doi:10.1186/s12935-025-03958-w · Cited by 1
“The role of Complex II in tumors is complex and context-dependent: it can promote tumor progression through succinate accumulation and activation of HIF-1α [37], while also inhibiting tumor growth by maintaining mitochondrial function and inducing apoptosis [17].”
Feng, J., Zhao, Y., Xu, M., et al. (2025) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2025.1675547 · Cited by 1
Pseudohypoxia induced by chemical pollutants: Biochemical evidence of environmental vulnerability
Hu, C., Tao, Z., Lin, Y., Chen, J., Ngeng, N. A., Aschner, M., Tinkov, A. A., & Lu, R. (2025) · Ecotoxicology and Environmental Safety · doi:10.1016/j.ecoenv.2025.119243 · Cited by 2
Protein succinylation in tumors-from biology to clinical therapy
Li, H., Zhang, H., Zhu, J., Tang, Y., & An, J. (2025) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2025.149489 · Cited by 2
Hereditary Renal Cancer Syndromes
Cornejo, K. M., Machacek, M. E., Lu, Z., Clemente, L. C., Liu, X., Nair, V., & Wu, C. (2026) · Advances in Anatomic Pathology · doi:10.1097/pap.0000000000000521 · Cited by 1
Sato, T., Isagawa, T., Sugiura, Y., Sawaki, D., Nakagama, Y., Kuchimaru, T., Minatsuki, S., Sato, S., Ono, K., Chuluun-Erdene, A., et al. (2026) · Journal of Pharmacological Sciences · doi:10.1016/j.jphs.2026.01.008 · Cited by 2
“26 Succinate is also a byproduct of ketone body metabolism.”
Succinate receptor 1 restricts hematopoiesis and prevents acute myeloid leukemia progression
Cuminetti, V., Boët, E., Heugel, M., Konieczny, J., Bernal, A., Gomez, M. J., Grimolizzi, F., Vilaplana‐Lopera, N., Ferré, M., Villatoro, A., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-68906-2 · Cited by 1
Zhang, Y., Yu, K., Fang, G., et al. (2026) · Journal of Cereal Science · doi:10.1016/j.jcs.2026.104435 · Cited by 1
Sánchez‐Castillo, A., Lommen, J. G. E., Consten, D., Savelkouls, K. G. M., Barbeau, L. M. O., Rouschop, K. M. A., Vooijs, M., & Kampen, K. R. (2026) · Cancer & Metabolism · doi:10.1186/s40170-026-00433-6 · Cited by 1
“For instance, increased concentrations of succinate, which is a by-product of HIFα hydroxylation and allosteric inhibitor of the PHD reaction, stabilizes HIF1α in normoxia [21].”
Liang, B. (2026) · Clinical bioenergetics · doi:10.3390/clinbioenerg2020009 · Cited by 1
“SDH-deficient tumors, including paragangliomas, pheochromocytomas, gastrointestinal stromal tumors, and renal cell carcinomas, are characteristically highly vascular, consistent with HIF-driven angiogenesis [54].”
InfluentialCoutinho, L. L., Palmieri, E. M., Ridnour, L. A., Cheng, R. Y. S., Heinz, W. F., Anderson, S. K., Billiar, T. R., Chang, J. C., Lockett, S., Rangel, M. C., et al. (2026) · Redox Biology · doi:10.1016/j.redox.2026.104245 · Cited by 2
“…and histone demethylases, promoting epigenetic changes that stabilize immunosuppressive programs, while succinate accumulation, largely glutamine-derived in NO-exposed macrophages, stabilizes HIF-1 α by inhibiting prolyl hydroxylases (PHDs), driving a pseudo-hypoxic transcriptional state [54 – 59].”
Górecka, K., Soboska, K., Pacholczyk, M., Pirola, L., & Balcerczyk, A. (2026) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-026-06264-4 · Cited by 1
“1), is a well-known inhibitor of prolyl hydroxylases and its accumulation leads to the stabilization and activation of HIF-1α when SDH (succi - nate dehydrogenase) is inhibited [67].”
Chen, W.-Y., Huang, K., Kajla, G., Wen, Y., Liu, M., Fan, Y. C., Dung, P. V. T., Yeh, H.-L., Chen, W.-H., Jiang, K.-C., et al. (2026) · Cell Communication and Signaling · doi:10.1186/s12964-026-02977-y · Cited by 1
“Elevated intracellular succinate competitively inhibits α-ketoglutarate-dependent prolyl hydroxylases (PHDs), thereby stabilizing HIF-1α under normoxic conditions, a state of pseudohypoxia that directly activates NED-associated gene programs [42].”
Zhang, W., Zhang, Y., Wang, X., Chen, Y., Li, Y., & Sun, Y. (2026) · Antioxidants · doi:10.3390/antiox15070845 · Cited by 1
“…-KGDD activity is compromised by oxidative stress, mitochondrial dysfunction, or AKG depletion, HIF-1 α aberrantly accumulates under normoxia—a state termed pseudohypoxia—which has been increasingly recognized as a maladaptive driver of metabolic reprogramming and mitochondrial dysfunction [24,25].”
Metadata
- 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
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2005-01
- Volume
- 7
- Issue
- 1
- Pages
- 77-85
- ISSN
- 1535-6108 (ISSN-L)
- 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
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-11, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-11 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
