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 measuredThe cited source says what the claim attributes to it.
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
“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
“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 2,001–2,100 of 2,106
Stevenson, E. R., O’Brien, J. P., Manuel, A. M., Uvalle, C. E., Buchan, G. J., Mullett, S. J., Lockwood, K. C., Suber, T. L., Freeman, B. Α., & Gelhaus, S. L. (2025) · Frontiers in Physiology · doi:10.3389/fphys.2025.1426102 · Cited by 1
The Caenorhabditis elegans sdhb-1(R244H) Model Shows Characteristics of Human PPGL Tumor Cells
Ősz, F., Akbar, M., Zsidó, B. Z., et al. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms262010185
“It is believed that in many cancer-linked SDH mutations mitochondrial succinate accumulates in the cytoplasm and activates HIF-1 α (hypoxia-inducible factor alpha), which favors pseudohypoxia-driven tumorigenesis through mal-activation of the target genes [11].”
Heher, P., Pfeiffer-Vogl, J., Ganassi, M., Fulea, R.-C., McGuire, L., Engquist, E. N., Tyszkiewicz, M., Prüller, J., Grillari, J., Tasca, G. A., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.11.25.690559 · Cited by 1
“Since HIF1α stabilisation and subsequent metabolic adaptation can be caused by mitoROS [63] and/or succinate build-up [64], we speculate that DUX4-HIF1α crosstalk could be also mediated by RET, which in turn could trigger a persistent pro-inflammatory muscle state by chronic activation of the…”
de Lapiscina, I. M., Baquero, C., & Castaño, L. (2025) · Vitamins and hormones · doi:10.1016/bs.vh.2025.10.008
Mapping the HIF Transcription Factor in Cancer by ChIP-Seq Technology
Schödel, J., & Mole, D. R. (2013) · Springer eBooks · doi:10.1007/978-1-4614-7645-0_5
Analyse und Modulation des Tumormetabolismus in humanen Tumorzelllinien und Tumorgeweben
Kastenberger, M. (2012) · University of Regensburg Publication Server (University of Regensburg) · doi:10.5283/epub.18413
Epigenetic dysregulation of novel candidate genes in melanoma
Wang, H. (2013) · Discovery Research Portal (University of Dundee)
DNA Oxidative Damage and Cancer
Stuart, J. A., & Page, M. M. (2008) · Humana Press eBooks · doi:10.1007/978-1-59745-420-9_12 · Cited by 1
Yang, J.-X., Chuang, Y.-C., Tseng, J.-C., Liu, Y.-L., Lai, C.-Y., Lee, A. Y., Huang, C.-Y. F., Hong, Y.-R., & Chuang, T.-H. (2024) · Figshare · doi:10.6084/m9.figshare.26047017
Wang, X., Xu, B., Du, J., Xia, J., Lei, G., Zhou, C., Hu, J., Zhang, Y., Chen, S., Shao, F., et al. (2022) · Figshare · doi:10.6084/m9.figshare.21332770
Wang, X., Xu, B., Du, J., Xia, J., Lei, G., Zhou, C., Hu, J., Zhang, Y., Chen, S., Shao, F., et al. (2022) · Figshare · doi:10.6084/m9.figshare.21332776
Wang, X., Xu, B., Du, J., Xia, J., Lei, G., Zhou, C., Hu, J., Zhang, Y., Chen, S., Shao, F., et al. (2022) · Figshare · doi:10.6084/m9.figshare.21332773
Wang, X., Xu, B., Du, J., Xia, J., Lei, G., Zhou, C., Hu, J., Zhang, Y., Chen, S., Shao, F., et al. (2022) · Figshare · doi:10.6084/m9.figshare.21332767
Modular to cyclic TCA governs hematopoiesis in DrosophilaPreprint
Tomar, A., Chakrabarti, S., & Mukherjee, T. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2025.12.04.692477
Wang, C., Yuan, M., Peng, J., et al. (2025) · Journal of Future Foods · doi:10.1016/j.jfutfo.2025.10.033
Li, P., Peng, H., Huang, Z., Sun, Z., Li, Y., Wu, S. P., Lin, L., Zhang, S., Li, H. C., & Cao, Y. (2026) · Frontiers in Microbiology · doi:10.3389/fmicb.2025.1643268
Hernández, M. I., Zugaza, J. L., & Martín, A. (2026) · Neural Regeneration Research · doi:10.4103/nrr.nrr-d-25-00794
“Since succinate inhibits PHDs that normally target HIF-α for degradation, succinylation of HIF-α lysine residues could further stabilize the protein by preventing its degradation, thereby enhancing the hypoxic response in this context (Selak et al., 2005).”
Saucedo-Rodríguez, M. J., Pecina, P., Tauchmannová, K., Čunátová, K., Vrbacký, M., Čajka, T., Houštěk, J., Mráček, T., & Pecinová, A. (2026) · Research Square · doi:10.21203/rs.3.rs-8568560/v1 · Cited by 1
Doherty, M., Feng, J., Wang, T., Yin, C., Byrne, N. M., Chambers, S. E. J., Islam, R., Lamprou, D. A., & Coulter, J. A. (2026) · ACS Biomaterials Science & Engineering · doi:10.1021/acsbiomaterials.5c02175 · Cited by 1
He, T., Zeng, Y., Zhou, J., Tian, Y., Wang, D., Ma, J., Liu, J., Wu, W., Wei, C., & Jiao, R. (2026) · Cell Reports · doi:10.1016/j.celrep.2025.116922
The Potential for Using the Mechanism of Hypoxic Adaptation in Lower Eukaryotes
Zorov, D. B., Zorova, L. D., Babenko, V. А., Semenovich, D. S., Ivanova, A. E., Zorov, S. D., Pevzner, I. B., Plotnikov, E. Y., Silachev, D. N., & Sukhikh, G. T. (2026) · Biochemistry (Moscow) Supplement Series A Membrane and Cell Biology · doi:10.1134/s1990747825700527
“…of succinate (particularly noticeable during an ischemic attack) can be pathogenic for several reasons, among which are pathological changes mediated by the succinate receptor, which can be par-BIOCHEMISTRY ticularly evident in oncogenesis, significantly contributing to metastasis [25–30].”
Vanova, K. H., Uher, O., Kraus, M., et al. (2025) · SSRN Electronic Journal · doi:10.2139/ssrn.5333398
TCA cycle intermediates as an adjunct strategy for human iPSC-derived cardiomyocyte maturation
Alagarsamy, K. N., Bueckert, E., Gupta, M., Aliani, M., & Dhingra, S. (2026) · BBA Advances · doi:10.1016/j.bbadva.2026.100183 · Cited by 1
“Furthermore, succinate and fumarate have been shown to stabilize hypoxia-inducible factor-1 α (HIF-1 α ) through inhibition of prolyl hydroxylase enzymes that further affect mitochondrial metabolism in the cells [46].”
DHODH turns cytosolic, yet cells keep growing
Vidal-Cruchez, O., & Ben‐Sahra, I. (2026) · Nature Metabolism · doi:10.1038/s42255-026-01466-3
Ruco, L. T. R., & Urrea-Orozco, A. F. (2026) · Revista Colombiana de Hematología y Oncología · doi:10.51643/22562915.828
Ni, X., Xia, P., Liang, M., Zhang, L. Q., Chen, J., He, Z., Huang, H., Feng, J., Niu, X., & Pu, F. (2026) · Genes & Diseases · doi:10.1016/j.gendis.2026.102111
Zebrafish pkm activates the Hif-1α signaling pathway and promotes metabolic reprogramming
Zhang, W., Liu, D., Zhou, J., Zu, C., Li, Y., Liu, C., Sun, X., Lu, L., & Liu, Y. (2026) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2026.153543
Bioenergetics of lung cancer predicts treatment response and adaptive capacityPreprint
Pérez-Valencia, J. A., Pätzold, A., & Plönes, T. (2026) · Research Square · doi:10.21203/rs.3.rs-9018282/v1
Piao, J., Yang, J., Li, Y., Yi, Y. A. N. G., Li, Z., Jin, G., Chai, J., & Wang, C. (2026) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2026.151492
Shaheeda, A., & Kabekkodu, S. P. (2026) · Cell Communication and Signaling · doi:10.1186/s12964-026-02845-9
Influence of hypoxia on tumour cell susceptibility to cytotoxic T lymphocyte mediated lysis
Noman, M. Z. (2012) · theses.fr (ABES) · doi:10.70675/306da2eez5bc3z478ez83c5zdc39407a896e
Métabolisme oxydatif et mitochondrial des cellules cancéreuses de prostate
Matar, C. (2011) · theses.fr (ABES) · doi:10.70675/6abb943ez119bz424fzbe51z3467241fc235
Influence de la Transition Epithélio-Mésenchymateuse sur la réponse T cytotoxique anti-tumorale
Akalay, I. (2013) · theses.fr (ABES) · doi:10.70675/cb446c70z6112z416ez9557z9831373b9e40
Metabolic fueling of hematopoietic stem cell differentiation to the erythroid lineage
Oburoglu, L. (2014) · theses.fr (ABES) · doi:10.70675/2a8ca582z1bd3z4b90z96c1z5964d1e426b9
Hammad, N. (2018) · theses.fr (ABES) · doi:10.70675/95e12429zc05bz4cd1za56ez80e5989decee
“En effet, il a été montré que l’IDH des cellules tumorales est capable de produire un nouveau métabolite : le 2-hydroxyglutarate (2-HG) à partir de l’α-cétoglutarate [60].”
Kaminski, L. (2018) · theses.fr (ABES) · doi:10.70675/7f6ae88bz4f3cz49d3zafcdz8682254b2be3
Role of VDAC1 hypoxic form, VDAC1-∆C, in the expression of primary cilia and tumor progression
Fabbri, L. (2019) · theses.fr (ABES) · doi:10.70675/7a53239dzc652z4ea4z8b95z4a71961c83b4
Targeting the metabolic environment to modulate T cell effector function
Matias, M. I. (2019) · theses.fr (ABES) · doi:10.70675/0582ddaaze61dz4707z9cb1zdb8fe1d82653
Chaddad, H. (2019) · theses.fr (ABES) · doi:10.70675/e2786a5az288az46d4za2afz98cdafddfe5b
Stage-specific changes in the Krebs cycle network regulate human erythroid differentiation
Romano, M. (2018) · theses.fr (ABES) · doi:10.70675/4312681cz0207z4923zb100z879f8a73681c
Rôle du transporteur mitochondrial UCP2 dans la leucémie
Sancerni, T. (2019) · theses.fr (ABES) · doi:10.70675/c0f1a3a3z992az4717zb426z210e51dadf82
Role of mitochondrial respiration in Listeria monocytogenes infection
Spier, A. (2021) · theses.fr (ABES) · doi:10.70675/cd44057azc986z44a5zbfd6zc91fa993e0bf
Impact du ciblage du domaine de liaison de HIF-1α avec HIF-1β sur le paysage immunitaire du mélanome
Lequeux, A. (2020) · theses.fr (ABES) · doi:10.70675/a29d12dbz79c1z4d37za978z2e2319131c82
Yoganathan, T. (2022) · theses.fr (ABES) · doi:10.70675/86147de9za574z463fzbad0z57552b0ff2a5
EVT-701 : targeting electron transport chain complex I as therapeutic approach in cancer
Yolba, R. L. (2021) · theses.fr (ABES) · doi:10.70675/9cadea77z03ccz4a54zb381zf34a432615a5
Impact des mutations SDH sur la réponse antitumorale et identification de nouveaux biomarqueurs
Lamy, C. (2021) · theses.fr (ABES) · doi:10.70675/036f6787z50daz43e6zbeafzbcebfb700048
The role of the GATOR1 complex in mitochondrial function and quality control
Zhang, H. (2025) · theses.fr (ABES) · doi:10.70675/1dad907cz4477z4068z81c2z087317cd244e
Golnarnik, G., Nieminen, A. I., Søland, T. M., Galtung, H. K., & Haug, T. M. (2026) · Biochemistry and Biophysics Reports · doi:10.1016/j.bbrep.2026.102596
“This energy demand is primarily met through the tricarboxylic acid cycle (TCA), a key metabolic pathway that oxidizes nutrients to fuel the electron transport chain (ETC) and oxidative phosphorylation (OXPHOS) for ATP generation [19].”
Nair, V., Minakawa, A., Smith, C., Berthier, C. C., Hartman, J., Menon, R., Fermin, D., Otto, E. A., Gisch, D. L., Eadon, M. T., et al. (2026) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-026-02653-0 · Cited by 1
“53 Transcripts of the TCA cycle are increased in T2D compared to controls and suppressed with SGLT2i, 54 and TCA cycle fl ux is increased in the kidneys of db/db mouse models of diabetes.”
Incidental intraprostatic paraganglioma: Case report and review of the literature
Gonzalez, D., Ryan, F., Kokoneshi, K., et al. (2026) · Urology Case Reports · doi:10.1016/j.eucr.2026.103444
“16 These syndromes are characterized by an increased risk of developing PGLs, pheochromocytomas, renal cell carcinoma, gastrointestinal stromal tumors, and pituitary adenomas.”
Huang, H., Ni, K., 李晨华, Cai, M., Liu, Y., Zhang, J., Shen, Y., Chen, Y., Sun, J., Shao, J., et al. (2026) · Cell Death and Disease · doi:10.1038/s41419-026-08757-3
Soliman, S. H. A., Fabritiis, S. D., Iwanaszko, M., Lin, L. A., Das, M., Gold, S. R., Andersen, G. D., Chakrabarty, R. P., Chandel, N. S., & Shilatifard, A. (2026) · Science Advances · doi:10.1126/sciadv.adz9295
Zheng, J., Guo, R., Zhang, R., Liu, X., Guo, R., Li, H., Wei, J., Zheng, Y., & Zhang, H. (2026) · Environmental Pollution · doi:10.1016/j.envpol.2026.128421
Molecular overview of major salivary gland carcinomas in chilean patients: 2 case reports
Veas-Torres, J., Miranda, D. I., Chávez, F. S., Sáez, M., Avendaño, M. E., Abello, C. S. M., Villanueva, M. G., Barriga, F. S., Brito, M. N., la Torre, P. R. D., et al. (2026) · BMC Oral Health · doi:10.1186/s12903-026-09517-7
Yu, J., Ding, L., Yang, Y., et al. (2026) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-026-06271-5
“SDHB loss is classically linked to paragangliomas and pheochromocytomas due to succinate accumulation and HIF-1α stabilization[ 27 ].”
Yin, J., Zhu, E., Zheng, X., Ha, X., & Li, B. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1801442 · Cited by 1
“The effect of hypoxia can be enhanced by pseudohypoxia (26 – 29), a phenomenon caused by cell metabolic changes after hypoxia.”
Luo, Y., Xin, Z., Liu, Y., Ren, R., & Wang, X. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27125348
Metabolic Subtypes Predict Treatment Response in Acute Myeloid Leukemia: A Pilot Study
Yan, C., Huang, Y., Cai, Q., et al. (2026) · Blood and Lymphatic Cancer Targets and Therapy · doi:10.2147/blctt.s612305
Kołodziejska, R., Godlewski, A., Tafelska‐Kaczmarek, A., Kuk, J., Moritz, M., Sergot, K., Kurhaluk, N., Ткаченко, Г. М., & Woźniak, A. (2026) · Cells · doi:10.3390/cells15121103
“Additionally, accumulation of TCA cycle metabolites such as succinate and fumarate inhibits PHDs by competing with α - ketoglutarate [118–120].”
Liu, Z., Zhang, Z., Yang, K., Ji, R., Mao, X., Niu, H., Chu, M., Wang, Y., & Zhao, J. (2026) · Research Square · doi:10.21203/rs.3.rs-9985262/v1
Pang, Y., Wang, Z., Liu, Y. L., Feng, C., Song, Y., Cao, S., Wang, D., Zhang, L., Lü, P., & Yu, L. (2026) · Toxicology · doi:10.1016/j.tox.2026.154532
Dysregulated calcium signaling underlies hyposalivation and microbial dysbiosis in Down syndrome
Son, G., Bomfim, G. H. S., Xu, F., Thomas, S. C., Rosenberg, K., Kim, T., Rice, E., Budjab, E., Jones, R., Wang, Y., et al. (2026) · Cell Reports · doi:10.1016/j.celrep.2026.117619
“35 Succinate can be transported from the mitochondria to the cytosol through a dicarboxylic acid transporter resulting in the stabilization and activation HIF-1 α , a process known as “pseudo-hypoxia” 89 and results in elevated levels of several pro-inflammatory cytokines.”
Singh, U., Albalawi, A. A., Manasra, R., Makharza, S. A., Emwas, A.-H., & Jaremko, M. (2026) · ACS Food Science & Technology · doi:10.1021/acsfoodscitech.5c00958
Lee, D. C., Duraj, T., Chinopoulos, C., & Seyfried, T. N. (2026) · Journal of Bioenergetics and Biomembranes · doi:10.1007/s10863-026-10117-x
“Notably, many cancer cells are in a constant pseudo-hypoxic state where HIF-1α is stabilized, in part, by cytosolic succinate accumulation (Selak et al., 2005; Bao et al., 2021 ).”
Li, M., & Mailloux, R. J. (2026) · Journal of Cellular Biochemistry · doi:10.1002/jcb.70104
“Thus, succinate accumulates during hypoxia and indirectly stabilizes HIF1‐α levels by inhibiting PHD2 activity [122].”
Niu, J., Sun, W., Gong, R., & Pan, Q. (2026) · Clinical & Translational Oncology · doi:10.1007/s12094-026-04496-1
Fan, Y., Wang, N., Zhao, C., & Zhang, Z. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1842560 · Cited by 1
“First, succinate inhibits the activity of Prolyl Hydroxylase (PHD), thereby preventing HIF-1 a from undergoing ubiquitin-mediated degradation (62, 63).”
Pedrosa, M. D. S., Ahn, J. A. O. K., Sears, J. D., Walker, K. A., Thurlow, L. R., Moorman, N. J., & Arthur, J. C. (2026) · Science Advances · doi:10.1126/sciadv.aeb7972
Liu, Y. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1872804
“In tumors with succinate dehydrogenase dysfunction, succinate links TCA-cycle disruption to pseudohypoxia by inhibiting HIF-alpha prolyl hydroxylases (65).”
Zhang, J., Tang, Z., Wang, Y., Wan, J., Zhou, Y., Li, J., & Ming, J. (2026) · Cells · doi:10.3390/cells15151422 · Cited by 1
“Since PHDs are responsible for hydroxylating pro-line residues on HIF-1 α to mark it for proteasomal degradation, succinate accumulation stabilizes HIF-1 α , thereby inducing the transcription of genes governing glycolysis and angiogenesis that ultimately fuel cancer progression [38].”
Jiménez, C., Waguespack, S. G., Kaplan, J., Habra, M. A., & Varghese, J. M. (2026) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgag324
Zhu, L., & Wu, B. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1899587 · Cited by 1
“Succinate can inhibit 2-oxoglutarate (2-OG) -dependent dioxygenases, including PHDs, primarily by altering the intracellular succinate-to-2-OG ratio and through product inhibition, thereby favoring HIF-1 a stabilization (11, 59 – 61).”
InfluentialMitochondrial Complex II in the regulation of immunopathology
Yamamoto, A., Sumii, Y., & Reddy, P. (2026) · Trends in Immunology · doi:10.1016/j.it.2026.07.013
Molecular clusters and precision medicine in pheochromocytomas and paragangliomas
Almeida, M. Q., Dahia, P. L. M., & Robledo, M. (2026) · Endocrine Related Cancer · doi:10.1530/erc-26-0258
Vivas, C. V., Batista, C. A., & Alencar, A. M. (2026) · Toxicology in Vitro · doi:10.1016/j.tiv.2026.106297
Zhou, Y., Bai, D., Li, Z., Li, C., Li, C., Chen, M., Guo, C., Yan, J., Han, Y., & Yang, Q. (2026) · Journal of Enzyme Inhibition and Medicinal Chemistry · doi:10.1080/14756366.2026.2719719
“…altered amino acid metabolic profiles, accompanied by elevations in metabolites such as succinate, ornithine, glutamine, and glutathione. this suggests that enhanced proline catabolism may further impact the tricarboxylic acid (tca) cycle, redox homeostasis, and amino acid metabolic networks 21 .”
Epigenetic reprogramming in autoimmune and immune-mediated skin disease
Bilik, S. M., Kraft, G., Sharifi, I., Hanly‐Jorda, F. M., Antonevich, S., Jimenez, J. J., & Satoh, T. K. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1915200
“In contrast, metabolites such as succinate and fumarate inhibit these enzymes, promoting accumulation of methylation marks (151 – 154).”
Wu, J.-Y., Chang, T.-C., Chen, M.-J., Cho, S.-H., Liou, J., Kuo, C.-C., & Wu, K. K. (2026) · Journal of Biomedical Science · doi:10.1186/s12929-026-01289-0
“Those findings are in keeping with the reports that SDHB mutations in PG/PC as well as SDHB silencing with siRNA in cancer cells cause loss of SDH activity and succinate accumulation [10, 11, 19].”
Oxygenaging: A Physiological Framework for Geroscience
Donegà, S., Fishbein, K. W., Dominelli, P. B., Herman, A. B., de Cabo, R., Gorospe, M., & Ferrucci, L. (2026) · Aging Cell · doi:10.1111/acel.70664
“Although mechanistically distinct, both routes converge on the same outcome, HIF-1α stabilization under normoxia (“Chronic Pseudohypoxia”) (Gomes et al. 2013; Selak et al. 2005).”
Luo, C., Li, T., Tak, J., DeBerge, M., Tsai, K., & Eltzschig, H. K. (2026) · Nature Reviews Cardiology · doi:10.1038/s41569-026-01339-y
Uncovering a Novel Role of the Apoptotic Initiator Caspase, Caspase-2
Johnson, S., & Lee, E. (2014) · DukeSpace (Duke University)
Zhang, Z., Wang, D., Lin, Q., Guo, P., & Wang, Z. (2026) · Biology · doi:10.3390/biology15171557
“This mechanism is well established in non-ovarian systems [34–36] (Figure 3).”
Bai, Y., & Chen, W. (2026) · Frontiers in Physiology · doi:10.3389/fphys.2026.1931732
“Similarly, succinate and fumarate, TCA cycle intermediates that accumulate upon disruption of OXPHOS, inhibit prolyl hydroxylases and thereby stabilize HIF-1 a even under normoxic conditions (Isaacs et al., 2005; Selak et al., 2005).”
Dimethylmalonate suppresses white adipocyte differentiation and ameliorates diet-induced obesity
Sato, Y., Morioka, Y., Amano, M., & Namba, T. (2026) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2026.154577
Tang, D., Li, Q., Tacchi, C., Banchi, M., & Bocci, G. (2026) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2026.189713
Precision therapeutic strategies for advanced gastrointestinal stromal tumors
Ooki, A., Osumi, H., Shimozaki, K., Udagawa, S., & Yamaguchi, K. (2026) · Cancer and Metastasis Reviews · doi:10.1007/s10555-026-10381-8
Tang, Z., Luo, R., Zhang, W., Cao, X., Lu, S., & Li, X. (2026) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2026.102621
Metabolites and cancer metastasis
Yang, S., Shi, S., Hou, J., Zhang, J., & Su, Z. (2026) · Oncogene · doi:10.1038/s41388-026-03930-6
Wang, J., Jin, N., Li, S., Wang, B., & Chen, X. (2026) · Frontiers in Pharmacology · doi:10.3389/fphar.2026.1961846
Leng, H., Zheng, Z., Li, R., Yuan, Q., Lv, S., Yan, D., & Wu, L. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1946009
Cancer-derived lactic acid as a potential upstream contributor to tumor hypoxia
Kang, N., & Wang, Y. Z. (2026) · Communications Biology · doi:10.1038/s42003-026-11151-6
The Effect of Isocitrate Dehydrogenase on the Epigenetics of Human Mitochondrial DNA
Strang, J. A. (2014) · VCU Scholars Compass (Virginia Commonwealth University) · doi:10.25772/xrr8-0228
“Multiple enzymes of the TCA cycle have been shown to be implicated in the progression of cancer including Succinate Dehydrogenase (SDH) (67) and Fumarate Hydratase (FH) (31).”
BackgroundInfluential
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
