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 701–800 of 2,106
Current management of succinate dehydrogenase–deficient gastrointestinal stromal tumors
Neppala, P., Banerjee, S., Fanta, P. T., Yerba, M., Porras, K., Burgoyne, A. M., & Sicklick, J. K. (2019) · Cancer and Metastasis Reviews · doi:10.1007/s10555-019-09818-0 · Cited by 61
Complexity of macrophage metabolism in infection
He, W., Heinz, A., Jahn, D., & Hiller, K. (2021) · Current Opinion in Biotechnology · doi:10.1016/j.copbio.2021.01.020 · Cited by 58
MDH2 produced OAA is a metabolic switch rewiring the fuelling of respiratory chain and TCA cycle
Molinié, T., Cougouilles, E., David, C., Cahoreau, E., Portais, J., & Mourier, A. (2022) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2022.148532 · Cited by 60
Zhang, F., Zhang, Y., Zhou, J., et al. (2024) · Molecular Medicine · doi:10.1186/s10020-024-00929-1 · Cited by 60
“PDH activity can promote the hydroxylation of HIF-1α and subsequent degradation by the proteome (Selak et al. 2005), thereby inhibiting synovial angiogenesis and leukocyte infiltration, which prevents joint damage.”
BackgroundDynamic states of the DNA repair enzyme AlkB regulate product release
Bleijlevens, B., Shivarattan, T., Flashman, E., Yang, Y., Simpson, P. J., Koivisto, P., Sedgwick, B., Schofield, C. J., & Matthews, S. (2008) · EMBO Reports · doi:10.1038/embor.2008.120 · Cited by 60
“…the activity of 2OG oxygenases, including the prolyl hydroxylase domain enzymes, involved in the hypoxic response through competition for binding with 2OG (Selak et al, 2005; Hewitson et al, 2007); this competition is proposed as a molecular explanation for the Warburg effect in cancer cells.”
BackgroundCyr, A. R., Hitchler, M. J., & Domann, F. E. (2012) · Antioxidants and Redox Signaling · doi:10.1089/ars.2012.4850 · Cited by 62
“Multiple groups have shown that PHD enzymes are perturbed by increased succinate and oxidative stress secondary to SDH activity loss, leading to a pseudo-hypoxic state in which HIF is stabilized in the absence of true hypoxia (1, 14, 40).”
BackgroundThe Crabtree and Warburg effects: Do metabolite-induced regulations participate in their induction?
Hammad, N., Rosas‐Lemus, M., Uribe‐Carvajal, S., Rigoulet, M., & Devin, A. (2016) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2016.03.034 · Cited by 61
“Succinate and fumarate, which are structurally similar, inhibit these enzymes through product inhibition, since it has been shown that the effects of both metabolites can be reversed by the addition of excess αKG in vitro and in vivo (60).”
BackgroundMitochondria and Hypoxia: Metabolic Crosstalk in Cell-Fate Decisions
Bargiela, D., Burr, S. P., & Chinnery, P. F. (2018) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2018.02.002 · Cited by 60
Gallardo, M. E., Moreno‐Loshuertos, R., López‐Menéndez, C., Casqueiro, M., Silva, J., Bonilla, F., de Córdoba, S. R., & Enrı́quez, J. A. (2006) · Human Mutation · doi:10.1002/humu.20338 · Cited by 60
“structural OXPHOS genes in cancer gained recently support with the demonstration that specific mutations in subunits C and D of complex II (SDHC; MIM] 602413 and SDHD; MIM] 602690) are responsible for hereditary paraganglioma (MIM]168000), and an interesting molecular link among the complex II deficiency and the promo…”
BackgroundSelak, M. A., Durán, R. V., & Gottlieb, E. (2006) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2006.05.015 · Cited by 59
Self-citationDu, Z., Liu, X., Chen, T., Gao, W., Wu, Z., Hu, Z., Wei, D., Gao, C., & Li, Q. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.02.037 · Cited by 56
Mitochondrial Redox Hubs as Promising Targets for Anticancer Therapy
Ippolito, L., Giannoni, E., Chiarugi, P., & Parri, M. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.00256 · Cited by 60
The Bidirectional Relationship Between Cancer Epigenetics and Metabolism
Izzo, L., Affronti, H. C., & Wellen, K. E. (2020) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-070820-035832 · Cited by 64
“Notably, combined activation of HIF2 and inhibition of TET enzymes mimics the metastatic phenotype seen in SDHB-mutant cells (Morin et al. 2020).”
BackgroundErlich, J. R., To, E. E., Luong, R., Liong, F., Liong, S., Oseghale, O., Miles, M. A., Bozinovski, S., Brooks, R. D., Vlahos, R., et al. (2022) · Antioxidants · doi:10.3390/antiox11081488 · Cited by 65
“Through breaks in the tricarboxylic acid (TCA) cycle and the accumulation of the metabolite succinate, HIF1-α is stabilised, and this can promote the upregulation of genes involved in glycolysis and also interleukin (IL)-1β [3,4].”
BackgroundPast, Present, and Future of Molecular and Cellular Oncology
Galluzzi, L., Vitale, I., & Kroemer, G. (2011) · Frontiers in Oncology · doi:10.3389/fonc.2011.00001 · Cited by 62
“Then, Selak et al. (2005) and Pollard et al. (2005) independently demonstrated that succinate and fumarate, accumulating in conditions of SDH and FH deficiency, respectively, inhibit prolyl hydroxylases in the cytosol leading to stabilization and activation of the oncoprotein HIF1α (Pollard et al.,…”
BackgroundInfluentialGlucose Modulates Respiratory Complex I Activity in Response to Acute Mitochondrial Dysfunction
Cannino, G., El‐Khoury, R., Pirinen, M., Hutz, B., Rustin, P., Jacobs, H. T., & Dufour, É. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.386060 · Cited by 62
“Interestingly, HIF1 stabilization can also be induced even in normoxic conditions by cytosolic accumulation of succinate and/or reactive oxygen species (8, 9), which are common although not universal consequences of mitochondrial OXPHOS dysfunction.”
BackgroundRao, J. U., Engelke, U. F. H., Rodenburg, R. J., Wevers, R. A., Pacák, K., Eisenhofer, G., Qin, N., Küsters, B., Goudswaard, A. G., Lenders, J. W. M., et al. (2013) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-3922 · Cited by 58
Hypoxia signaling during acute lung injury
Vohwinkel, C. U., Hoegl, S., & Eltzschig, H. K. (2015) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00226.2015 · Cited by 58
Long-term High Fat Ketogenic Diet Promotes Renal Tumor Growth in a Rat Model of Tuberous Sclerosis
Liśkiewicz, A., Liśkiewicz, D., Wojakowska, A., Polański, K., Lewin‐Kowalik, J., Kotulska, K., & Jędrzejowska–Szypułka, H. (2016) · Scientific Reports · doi:10.1038/srep21807 · Cited by 58
Степанова, А., Shurubor, Y. I., Valsecchi, F., Manfredi, G., & Galkin, A. S. (2016) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2016.06.002 · Cited by 58
Liu, Y., Munoz, N. M., Tsai, A., Logan, T. M., & Ma, T. (2016) · Stem Cells · doi:10.1002/stem.2510 · Cited by 60
Genetic Aspects of Pituitary Adenomas
Marques, P., & Korbonits, M. (2017) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/j.ecl.2017.01.004 · Cited by 60
Zhao, C., Mirando, A. C., Sové, R. J., Medeiros, T. X., Annex, B. H., & Popel, A. S. (2019) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1007468 · Cited by 62
Molecular Biology of Renal Cell Cancer and the Identification of Therapeutic Targets
Iliopoulos, O. (2006) · Journal of Clinical Oncology · doi:10.1200/jco.2006.08.8948 · Cited by 59
Máximo, V., Lima, J. P., Soares, P., & Sobrinho-Simões, M. A. (2009) · Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin · doi:10.1007/s00428-009-0766-2 · Cited by 60
“The role played by the increased activity of HIF-1α in cancer development has been repeatedly aknowledged both in connection with mitochondrial alterations [32, 57, 120] and in other settings [115–119].”
BackgroundHypoxia and the endometrium: An indispensable role for HIF-1α as therapeutic strategies
Dai, W., Guo, R., Na, X., Jiang, S., Liang, J., Guo, C., Fang, Y., Na, Z., & Li, D. (2024) · Redox Biology · doi:10.1016/j.redox.2024.103205 · Cited by 67
“The prolyl hydroxylase, containing oxygen and 2-oxoglutarate as its substrates, also triggers the prolyl hydroxylation of HIF-1 α , maintaining low levels of HIF-1 α under normoxic states [127].”
BackgroundSuccinate dehydrogenase deficiency in pediatric and adult gastrointestinal stromal tumors
Belinsky, M. G. (2013) · Frontiers in Oncology · doi:10.3389/fonc.2013.00117 · Cited by 61
“In normoxic conditions, PHD catalyzes the hydroxylation of HIFα, which facilitates binding to the VHL (von Hippel–Lindau) gene product and targeting of the HIFα for ubiquitination and proteasomal degradation.”
BackgroundInfluentialLi, J., Yang, Y., Li, L., Zhang, L., Liu, Q., Liu, K., Li, P., Liu, B., & Qi, L. (2017) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2017.07.017 · Cited by 55
Chemically induced pheochromocytomas in rats: mechanisms and relevance for human risk assessment
Greim, H. A., Hartwig, A., Reuter, U., Richter-Reichhelm, H.-B., & Thielmann, H. W. (2009) · Critical Reviews in Toxicology · doi:10.1080/10408440903190861 · Cited by 61
“It is thus possible to demonstrate a regulatory coupling between the reduced activity of succinate dehydrogenase or fumarate hydratase on the one hand and an increased effect of the hypoxia-inducible transcription factors on the other hand (Gottlieb & Tomlinson, 2005; Selak et al., 2005).”
BackgroundComparative Biology of Oxygen Sensing in Plants and Animals
Holdsworth, M. J., & Gibbs, D. J. (2020) · Current Biology · doi:10.1016/j.cub.2020.03.021 · Cited by 56
The Warburg effect and mitochondrial oxidative phosphorylation: Friends or foes?
Pinto, M. M., Paumard, P., Bouchez, C. L., Ransac, S., Duvezin‐Caubet, S., Mazat, J., Rigoulet, M., & Devin, A. (2022) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2022.148931 · Cited by 56
DNA repair pathways and mitochondrial DNA mutations in gastrointestinal carcinogenesis
Basso, D., Navaglia, F., Fogar, P., Zambon, C., Greco, E., Schiavon, S., Fasolo, M., Stranges, A., Falda, A., Padoan, A., et al. (2007) · Clinica Chimica Acta · doi:10.1016/j.cca.2007.02.020 · Cited by 57
“An enhanced production of oxygen-free radicals (ROS) and succinate in response to energy depletion, might favor cell growth, angiogenesis and metastases, through the transactivation of several nuclear genes induced by HIF-α [36].”
BackgroundChoi, J. S., Baek, H., Kim, S., Kim, M. J., Youk, J. H., Moon, H. J., Kim, E., Han, K., Kim, D., Kim, S. I., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0051712 · Cited by 57
“Besides these markers, Ala, Suc, and several polyunsaturated fatty acids were reported as biomarkers related to metabolism in cancer [34,42,43].”
BackgroundGenetic basis of phaeochromocytoma and paraganglioma
Benn, D. E., & Robinson, B. G. (2006) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2006.07.005 · Cited by 55
Hypoxia‐inducible factor signalling mechanisms in the central nervous system
Corcoran, A., & O'Connor, J. J. (2013) · Acta Physiologica · doi:10.1111/apha.12117 · Cited by 58
Model animals for the study of oxidative stress from complex II
Ishii, T., Miyazawa, M., Onouchi, H., Yasuda, K., Hartman, P. S., & Ishii, N. (2012) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2012.10.016 · Cited by 60
Conceptual Framework for Cutting the Pancreatic Cancer Fuel Supply
Le, A., Rajeshkumar, N. V., Maitra, A., & Dang, C. V. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-0041 · Cited by 57
“enzymes, suchas succinate dehydrogenase (SDH), fumarate hydratase (FH), and isocitrate dehydrogenase (IDH) have also been linked to tumorigenesis, underscoring the intimate connections betweenmetabolismand cancer (11, 12).”
BackgroundGermline and mosaic mutations causing pituitary tumours: genetic and molecular aspects
Pepe, S., Korbonits, M., & Iacovazzo, D. (2018) · Journal of Endocrinology · doi:10.1530/joe-18-0446 · Cited by 58
Park, J.-H., Shim, D., Kim, K. E. S., Lee, W., & Shin, S. J. (2021) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2021.635335 · Cited by 57
Mitochondrial-targeted nanoparticles: Delivery and therapeutic agents in cancer
Ganji, C., Muppala, V., Khan, M., Nagaraju, G. P., & Farran, B. (2022) · Drug Discovery Today · doi:10.1016/j.drudis.2022.103469 · Cited by 57
The mitochondrial carrier SLC25A10 regulates cancer cell growth
Zhou, X., Paredes, J. A., Krishnan, S., Curbo, S., & Karlsson, A. (2015) · Oncotarget · doi:10.18632/oncotarget.3375 · Cited by 57
“Anti-p21, anti-HIF-1α, anti-β-actin were from Sigma (St. Louis, MO) and anti-VDAC/porin were from Abcam (Cambridge, UK).”
BackgroundInfluentialA comparison of hyperbaric oxygen versus hypoxic cerebral preconditioning in neonatal rats
Freiberger, J. J., Suliman, H. B., Sheng, H., et al. (2006) · Brain Research · doi:10.1016/j.brainres.2005.12.088 · Cited by 56
Citric Acid Cycle Intermediates in Cardioprotection
Czibik, G., Steeples, V., Yavari, A., & Ashrafian, H. (2014) · Circulation Cardiovascular Genetics · doi:10.1161/circgenetics.114.000220 · Cited by 58
Precision medicine in pheochromocytoma and paraganglioma: current and future concepts
Björklund, P., Pacák, K., & Crona, J. (2016) · Journal of Internal Medicine · doi:10.1111/joim.12507 · Cited by 59
Wentzel, J. F., Lewies, A., Bronkhorst, A. J., van Dyk, E., Plessis, D., & Pretorius, P. J. (2017) · Biochimie · doi:10.1016/j.biochi.2017.01.004 · Cited by 55
Fumarase: From the TCA Cycle to DNA Damage Response and Tumor Suppression
Leshets, M., Silas, Y., Lehming, N., & Pines, O. (2018) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2018.00068 · Cited by 57
“In the first, the loss of fumarase is suggested to block the TCA cycle in mitochondria causing the accumulation of fumarate, which subsequently leads to the stabilization of HIF (Isaacs et al., 2005; Pollard et al., 2005; Selak et al., 2005; Vanharanta et al., 2006).”
BackgroundRedox Signaling from Mitochondria: Signal Propagation and Its Targets
Ježek, P., Holendová, B., & Plecitá‐Hlavatá, L. (2020) · Biomolecules · doi:10.3390/biom10010093 · Cited by 59
“In any case, inhibition of PHDs is essential for HIF responses and might be also ensured simply either by competitive inhibition of PHD cofactors by the accumulated Krebs cycle metabolites [159,161,162] or metabolites such as L‐2‐hydroxyglutarate [163]; or by the lack of PHD co‐substrate 2OG.”
BackgroundInsights into the New Cancer Therapy through Redox Homeostasis and Metabolic Shifts
Hyun, D. (2020) · Cancers · doi:10.3390/cancers12071822 · Cited by 58
“In addition, impairments in the citric acid cycle, such as abnormal succinate dehydrogenase, are linked to oncogenesis [104].”
BackgroundMetabolic control of cellular immune-competency by odors in Drosophila
Madhwal, S., Shin, M., Kapoor, A., Goyal, M., Joshi, M. K., Pirzada, M. U. R., Gor, K., Shim, J., & Mukherjee, T. (2020) · eLife · doi:10.7554/elife.60376 · Cited by 59
Dioxygenases as O2-dependent regulators of the hypoxic response pathway
Dann, C. E., & Bruick, R. K. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.08.140 · Cited by 56
Lizárraga, D., Vinardell, M. P., Noé, V., van Delft, J. H. M., Alcarraz‐Vizán, G., Breda, S. G. J. V., Staal, Y. C. M., Günther, U. L., Reed, M. A. C., Ciudad, C. J., et al. (2011) · Journal of Nutrition · doi:10.3945/jn.110.133199 · Cited by 55
“Regarding the TCA cycle, downregulation of succinate-CoA ligase avoids the accumulation of succinate, a metabolite related to the stabilization and activation of hypoxia inducible factor 1, a-subunit (HIF-1a) (34), which activates the transcription of genes involved in crucial aspects of cancer biology (35).”
BackgroundAstuti, D., Ricketts, C. J., Chowdhury, R., McDonough, M. A., Gentle, D., Kirby, G. A., Schlisio, S., Kenchappa, R. S., Carter, B. D., Kaelin, W. G., et al. (2010) · Endocrine Related Cancer · doi:10.1677/erc-10-0113 · Cited by 56
“…accumulation of succinate and resulting inhibition of prolyl hydroxylase enzymes that are necessary for proteasomal degradation of HIF-a subunits (Selak et al. 2005), succinate accumulation may also inhibit other 2-oxoglutarate-dependent enzyme superfamily members which may also contribute to…”
BackgroundSuccinate Dehydrogenase and Ribonucleic Acid Networks in Cancer and Other Diseases
Moreno, C., Santos, R. M., Burns, R., & Zhang, W. C. (2020) · Cancers · doi:10.3390/cancers12113237 · Cited by 56
“Stabilized HIF increases malignant cell proliferation by promoting angiogenesis [25] and ROS production [2].”
BackgroundMetabolic regulation in the immune response to cancer
Wu, Q., Yu, X., Li, J., Sun, S., & Tu, Y. (2021) · 癌症：英文版 · doi:10.1002/cac2.12182 · Cited by 57
“HIF-1 also promotes tumor progression via other pathways, including cell immortalization, stem cell maintenance, genetic instability, and chemotherapy resistance, by directly or indirectly regulating the transcription of multiple target genes [177].”
BackgroundInfluentialZheng, S., Liu, Q., Liu, T., & Lu, X. (2021) · Journal of Physiology and Biochemistry · doi:10.1007/s13105-021-00813-0 · Cited by 54
Carney Triad, Carney-Stratakis Syndrome, 3PAS and Other Tumors Due to SDH Deficiency
Pitsava, G., Settas, N., Faucz, F. R., & Stratakis, C. A. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.680609 · Cited by 58
Hypoxia-Inducible Factor 1α and Its Role in Lung Injury: Adaptive or Maladaptive
Suresh, M. V., Balijepalli, S., Solanki, S. A., Aktay, S. L., Choudhary, K., Shah, Y. M., & Raghavendran, K. (2023) · Inflammation · doi:10.1007/s10753-022-01769-z · Cited by 59
“PHD activity is blocked by succinate and fumarate, stabilizing HIF-1α activity [37].”
BackgroundManganese Superoxide Dismutase: Structure, Function, and Implications in Human Disease
Grujičić, J., & Allen, A. R. (2025) · Antioxidants · doi:10.3390/antiox14070848 · Cited by 63
Extended Ischemia Prevents HIF1α Degradation at Reoxygenation by Impairing Prolyl-hydroxylation
Serra‐Pérez, A., Planas, A. M., Núñez-O’Mara, A., Berra, E., García‐Villoria, J., Ribes, A., & Santalucı́a, T. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.101048 · Cited by 55
Succinate dehydrogenase-deficient gastrointestinal stromal tumors
Wang, Y. (2015) · World Journal of Gastroenterology · doi:10.3748/wjg.v21.i8.2303 · Cited by 55
Paddenberg, R., König, P., Faulhammer, P., Goldenberg, A., Pfeil, U., & Kummer, W. (2006) · Respiratory Research · doi:10.1186/1465-9921-7-93 · Cited by 54
“For instance, succinate inhibits prolyl hydroxylases that, in an oxygen-dependent manner, regulate the stability of hypoxia-inducible transcription factor [46], and succinate can also interfere with neurotransmitter receptors [47].”
BackgroundEnergy metabolism in neuroblastoma and Wilms tumor.
Aminzadeh-Gohari, S., Vidali, S., Sperl, W., Kofler, B., & Feichtinger, R. G. (2015) · PubMed · doi:10.3978/j.issn.2224-4336.2015.01.04 · Cited by 56
“Accumulation of succinate, the substrate of SDH, correlates with stability of HIF-1α via inhibition of the HIF-alpha prolyl hydroxylases activity (67).”
BackgroundOu, T., Yang, W., Li, W., Lu, Y., Dong, Z., Zhu, H., Sun, X., Dong, Z., Weng, X., Chang, S., et al. (2020) · Clinical and Translational Medicine · doi:10.1002/ctm2.172 · Cited by 53
Structural basis for malfunction in complex II
Iverson, T. M., Maklashina, E., & Cecchini, G. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.r112.408419 · Cited by 53
“Interestingly, in yeast, themutants secreted succinate (65), consistent with reduced complex II activity elevating succinate levels and stabilizing hypoxia-inducible factor-1 , leading to a pseudohypoxic phenotype (40, 42).”
BackgroundOncometabolites at the crossroads of genetic, epigenetic and ecological alterations in cancer
Lanzetti, L. (2024) · Cell Death and Differentiation · doi:10.1038/s41418-024-01402-6 · Cited by 57
Succinate Dehydrogenase Loss in Familial Paraganglioma: Biochemistry, Genetics, and Epigenetics
Her, Y. F., & Maher, L. J. (2015) · International Journal of Endocrinology · doi:10.1155/2015/296167 · Cited by 53
The role of mitochondria in the oncogenic signal transduction
Frezza, C. (2014) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2013.12.013 · Cited by 53
Tomitsuka, E., Kita, K., & Esumi, H. (2009) · Proceedings of the Japan Academy Series B · doi:10.2183/pjab.85.258 · Cited by 51
Protein lysine acetylation guards metabolic homeostasis to fight against cancer
Xu, W., Li, Y., LIU, C., & Zhao, S. (2013) · Oncogene · doi:10.1038/onc.2013.163 · Cited by 53
α-Ketoglutarate abrogates the nuclear localization of HIF-1α in aluminum-exposed hepatocytes
Mailloux, R. J., Puiseux‐Dao, S., & Appanna, V. D. (2008) · Biochimie · doi:10.1016/j.biochi.2008.10.014 · Cited by 53
Pithukpakorn, M., Wei, M.-H., Toure, O., Steinbach, P. J., Glenn, G. M., Zbar, B., Linehan, W. M., & Toro, J. R. (2006) · Journal of Medical Genetics · doi:10.1136/jmg.2006.041087 · Cited by 55
The effect of immunosuppressive molecules on T-cell metabolic reprogramming
Fernández-Ramos, A. A., Poindessous, V., Marchetti, C., Pallet, N., & Loriot, M. (2016) · Biochimie · doi:10.1016/j.biochi.2016.04.016 · Cited by 53
Wang, H., Huwaimel, B., Verma, K., Miller, J. E., Germain, T., Kinarivala, N., Pappas, D., Brookes, P. S., & Trippier, P. C. (2017) · ChemMedChem · doi:10.1002/cmdc.201700196 · Cited by 52
Current and upcoming mitochondrial targets for cancer therapy
Kim, H. K., Noh, Y. H., Nilius, B., Ko, K. S., Rhee, B. D., Kim, N., & Han, J. (2017) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2017.06.006 · Cited by 52
Hypoxic Signalling in Tumour Stroma
Laitala, A., & Erler, J. T. (2018) · Frontiers in Oncology · doi:10.3389/fonc.2018.00189 · Cited by 55
From macrophage to osteoclast – How metabolism determines function and activity
Kubatzky, K. F., Uhle, F., & Eigenbrod, T. (2018) · Cytokine · doi:10.1016/j.cyto.2018.06.013 · Cited by 52
Pathobiological Pseudohypoxia as a Putative Mechanism Underlying Myelodysplastic Syndromes
Hayashi, Y., Zhang, Y., Yokota, A., Yan, X., Liu, J., Choi, K., Li, B., Sashida, G., Peng, Y., Xu, Z., et al. (2018) · Cancer Discovery · doi:10.1158/2159-8290.cd-17-1203 · Cited by 54
“It has been well documented that the SDH inactivation causes HIF stabilization (29, 30).”
BackgroundHIF-1α and HIF-2α Differently Regulate the Radiation Sensitivity of NSCLC Cells
Roig, E. M., Groot, A. J., Yaromina, A., Hendrickx, T. C., Barbeau, L. M. O., Giuranno, L., Dams, G., Ient, J., Pimentel, V. O., van Gisbergen, M. W., et al. (2019) · Cells · doi:10.3390/cells8010045 · Cited by 56
Park, Y.-K., Ahn, D., Oh, M., Tae-Kyoung, L., Yang, E. G., Son, M., & Park, H. (2008) · Molecular Pharmacology · doi:10.1124/mol.108.045278 · Cited by 52
“For PHDs, succinate as a product is a competitive inhibitor of -ketoglutarate, the substrate (Selak et al., 2005; Pan et al., 2007).”
BackgroundMitochondria in Neutrophil Apoptosis
van Raam, B. J., Verhoeven, A. J., & Kuijpers, T. W. (2006) · International Journal of Hematology · doi:10.1532/ijh97.06131 · Cited by 53
“Low oxygen tension or an increase in succinate levels due to failing respiratory chain activity leads to stabilization of the subunit and consequent activation of HIF-1 [70, 71 ].”
BackgroundMacrophages harness hepatocyte glutamate to boost liver regeneration
Rigual, M. D. M., Angulo-Aguado, M., Zagorac, S., Álvarez-Díaz, R., Benítez-Mondéjar, M., Yi, F., Martínez-Garay, C., Santos-de-Frutos, K., Kim, E., Campos-Olivas, R., et al. (2025) · Nature · doi:10.1038/s41586-025-08778-6 · Cited by 53
Hu, Y., Kirito, K., Yoshida, K., Mitsumori, T., Nakajima, K., Nozaki, Y., Hamanaka, S., Nagashima, T., Kunitama, M., Sakoe, K., et al. (2009) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-09-0150 · Cited by 52
“In contrast, HIF-1 is frequently activated in cancer cells, including under normoxic conditions (3), by oncogene products, impaired activity of tumor suppressor genes (4), or the accumulation of metabolic glucose intermediates (5, 6).”
BackgroundOwens, K. M., Aykin‐Burns, N., Dayal, D., Coleman, M. C., Domann, F. E., & Spitz, D. R. (2011) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2011.10.435 · Cited by 52
Lee, K., Lynd, J. D., O’Reilly, S., Kiupel, M., McCormick, J. J., & LaPres, J. J. (2008) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-07-2113 · Cited by 52
Auslander, N., Cunningham, C. E., Toosi, B. M., McEwen, E., Yizhak, K., Vizeacoumar, F. S., Parameswaran, S., Gonen, N., Freywald, T., Bhanumathy, K. K., et al. (2017) · Molecular Systems Biology · doi:10.15252/msb.20177739 · Cited by 51
“Other metabolic alterations are more tumor specific; different tumors differ in their dependence on glutamine (Son et al, 2013), serine (Possemato et al, 2011), or TCA cycle function (Selak et al, 2005; Dang et al, 2010).”
BackgroundRole of the mitochondrial stress response in human cancer progression
Wang, S., Chen, S., Tseng, L., & Lee, H. (2020) · Experimental Biology and Medicine · doi:10.1177/1535370220920558 · Cited by 51
Multifaceted Roles of Mitochondrial Components and Metabolites in Metabolic Diseases and Cancer
Nakhle, J., Rodriguez, A., & Vignais, M. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21124405 · Cited by 52
“The R22X nonsense SDHD mutation leads to succinate accumulation, which inhibits the activity of prolyl hydroxylase (PHD) and, consequently, induces HIF1α stabilization [65].”
BackgroundKhan, Z., Michalopoulos, G. K., & Stolz, D. B. (2006) · American Journal Of Pathology · doi:10.2353/ajpath.2006.060360 · Cited by 52
Mitochondria mediated cell death in diabetes
Szabadkai, G., & Duchen, M. R. (2009) · APOPTOSIS · doi:10.1007/s10495-009-0363-5 · Cited by 54
“Then again, both apoptotic and survival pathways target glycolysis, fatty acid metabolism and OXPHOS related enzymes (p53 [137–139], Akt/PK-B [140], HIF-1a/SDH [141], phosphotyrosine binding and regulation of PK [142]), indicating that specific changes in metabolic pathways might directly initiate mitochondrial apopto…”
BackgroundYu, Y., Cai, W., Zhou, J., Lu, H., Wang, Y., Song, Y., He, R., Pei, F., Wang, X., Zhang, R., et al. (2020) · International Immunopharmacology · doi:10.1016/j.intimp.2020.106830 · Cited by 52
Mitochondrial dysfunction, UPRmt signaling, and targeted therapy in metastasis tumor
Keerthiga, R., Pei, D., & Fu, A. (2021) · Cell & Bioscience · doi:10.1186/s13578-021-00696-0 · Cited by 53
Metabolite itaconate in host immunoregulation and defense
Yang, W., Wang, Y., Tao, K., & Li, R. (2023) · Cellular & Molecular Biology Letters · doi:10.1186/s11658-023-00503-3 · Cited by 58
“Accumulation of succinate resulting from SDH oxidation can promote the excessive production of reducing coenzyme Q, leading to the generation of mitochondrial ROS (mtROS) and inhibition of IL-10 expression [54, 55].”
BackgroundMetabolic alterations in hereditary and sporadic renal cell carcinoma
Coffey, N. J., & Simon, M. C. (2024) · Nature Reviews Nephrology · doi:10.1038/s41581-023-00800-2 · Cited by 56
Self-citationThe role of glucose metabolism and glucose-associated signalling in cancer.
Wittig, R., & Coy, J. F. (2008) · PubMed Central · Cited by 56
The genetic landscape of gastrointestinal stromal tumor lacking KIT and PDGFRA mutations
Boikos, S. A., & Stratakis, C. A. (2014) · Endocrine · doi:10.1007/s12020-014-0346-3 · Cited by 51
Castro, B. D., Pintado, C. O., García‐Flores, P., López‐Barneo, J., & Piruat, J. I. (2012) · Molecular and Cellular Biology · doi:10.1128/mcb.00128-12 · Cited by 51
“stabilization and nuclear translocation in normoxia (8, 41, 51).”
BackgroundThe role of PHD2 mutations in the pathogenesis of erythrocytosis
Gardie, B., Percy, M. J., Hoogewijs, D., Chowdhury, R., Bento, C., McMullin, M. F., Schofield, C. J., Lee, F. S., Richard, S., Arsenault, P. R., et al. (2014) · Hypoxia · doi:10.2147/hp.s54455 · Cited by 53
Yang, C., Matro, J. C., Huntoon, K. M., Ye, D. Y., Huynh, T., Fliedner, S. M. J., Breza, J., Jr., Zhuang, Z., & Pacák, K. (2012) · The FASEB Journal · doi:10.1096/fj.12-210146 · Cited by 52
Altered Hypoxic–Adenosine Axis and Metabolism in Group III Pulmonary Hypertension
Garcia‐Morales, L. J., Chen, N., Weng, T., Luo, F., Davies, J., Philip, K., Volcik, K. A., Melicoff, E., Amione‐Guerra, J., Bunge, R. R., et al. (2015) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2015-0145oc · Cited by 52
Decoding Warburg's hypothesis: tumor-related mutations in the mitochondrial respiratory chain
García-Heredia, J. M., & Carnero, A. (2015) · Oncotarget · doi:10.18632/oncotarget.6057 · Cited by 53
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
