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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
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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.
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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.
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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.
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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.
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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.
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- 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.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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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.
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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.
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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
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Sorted by citations
Items 1,401–1,500 of 2,106
Spera, I., Sánchez‐Rodríguez, R., Favia, M., Menga, A., Venegas, F. C., Angioni, R., Munari, F., Lanza, M., Campanella, A., Pierri, C. L., et al. (2021) · Cancers · doi:10.3390/cancers13215478 · Cited by 13
Model systems in SDHx-related pheochromocytoma/paraganglioma
Takács‐Vellai, K., Farkas, Z., Ősz, F., & Stewart, G. W. (2021) · Cancer and Metastasis Reviews · doi:10.1007/s10555-021-10009-z · Cited by 16
Sun, L., Kim, S. E., Mori, R., Miyaji, N., Nikawa, T., & Hirasaka, K. (2022) · Marine Drugs · doi:10.3390/md20110660 · Cited by 15
“The activation and stabilization of HIF-1α decreases mitochondria OCR while increasing glycolysis [54,55].”
BackgroundQuiroga, J., Alarcón, P., Ramírez, M. F., Manosalva, C., Teuber, S., Carretta, M. D., & Burgos, R. A. (2023) · Developmental & Comparative Immunology · doi:10.1016/j.dci.2023.104728 · Cited by 14
Tissue-specific macrophage immunometabolism
Ben-Arosh, H., & Avraham, R. (2023) · Current Opinion in Immunology · doi:10.1016/j.coi.2023.102369 · Cited by 15
Tuthill, M. H., Barod, R., Pyle, L., Cook, T., Chew, S. L., Gore, M. E., Maxwell, P. H., & Eisen, T. G. (2009) · BMJ Case Reports · doi:10.1136/bcr.08.2008.0732 · Cited by 14
Proteomics and metabolomics in cancer drug development
D’Alessandro, A., & Zolla, L. (2013) · Expert Review of Proteomics · doi:10.1586/14789450.2013.840440 · Cited by 14
A high-throughput analysis of the IDH1(R132H) protein expression in pituitary adenomas
Casar‐Borota, O., Øystese, K. A., Sundström, M., Melchior, L. C., & POPOVIC, V. M. (2016) · Pituitary · doi:10.1007/s11102-016-0720-7 · Cited by 14
“lation of HIF-1 [7, 23, 24], one can hypothesize that IDH mutations may play a pathogenic role in pituitary”
BackgroundInfluentialTeng, C., Kuo, H., & Sze, C. (2013) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2013.07.009 · Cited by 14
“…the mechanism of CIL-102's action, a basic study was conducted to demonstrate what could be a novel role of FUMH in the regulation of the tricarboxylic acid (TCA) cycle and advantages of influenced glycolysis in mitochondria of glioma cells by CIL-102 (King et al., 2006; Selak et al., 2005).”
BackgroundContributions of molecular analysis to the diagnosis and treatment of gastrointestinal neoplasms
Bellizzi, A. M. (2013) · Seminars in Diagnostic Pathology · doi:10.1053/j.semdp.2013.11.001 · Cited by 14
Ghosh, S., Dungdung, S. R., Choudhury, S. T., Chakraborty, S., & Das, N. (2013) · Nanomedicine · doi:10.2217/nnm.13.56 · Cited by 14
Tang, Z., Cao, T., Lin, S., et al. (2016) · Talanta · doi:10.1016/j.talanta.2016.01.056 · Cited by 14
Oxygen sensing and stem cell activation in the hypoxic carotid body
López‐Barneo, J. (2018) · Cell and Tissue Research · doi:10.1007/s00441-017-2783-9 · Cited by 14
“Therefore, it seems that SdhD ablation in mice, which can cause succinate accumulation, prolyl hydroxylase (PHD) inhibition and hypoxia inducible factor (HIF) stabilization (Selak et al. 2005; Millan-Ucles et al. 2014), is not sufficient to induce paragangliomas.”
BackgroundImmuno-metabolic changes in herpes virus infection
Chattopadhyay, D., Mukhopadhyay, A., Ojha, D., Sadhukhan, P. C., & Dutta, S. (2018) · Cytokine · doi:10.1016/j.cyto.2018.06.028 · Cited by 16
Oncometabolite induced primary cilia loss in pheochromocytoma
O’Toole, S. M., Watson, D., Novoselova, T. V., Romano, L. E. L., King, P., Bradshaw, T. Y., Thompson, C. L., Knight, M. M., Sharp, T. V., Barnes, M. R., et al. (2018) · Endocrine Related Cancer · doi:10.1530/erc-18-0134 · Cited by 14
Self-citationTherapies targeting the signal pathways of pheochromocytoma and paraganglioma
Liu, Y., Liu, L., & Zhu, F. (2019) · OncoTargets and Therapy · doi:10.2147/ott.s219056 · Cited by 14
“The mutations of FH result in the accumulation of fumarate, and thus activate the oncogenic HIF pathway through inhibiting PHD2.”
BackgroundInfluentialThe Redox-Metabolic Couple of T Lymphocytes: Potential Consequences for Hypertension
Moshfegh, C. M., & Case, A. J. (2020) · Antioxidants and Redox Signaling · doi:10.1089/ars.2020.8042 · Cited by 13
“These metabolites and ROS inhibit many a-ketoglutarate-dependent hydroxylases, demonstrated to alter epigenetic modifications (82, 144, 183).”
BackgroundWang, Z., Chen, H., Xue, L., He, W., Shu, W., Wu, H., & Wang, Z. (2021) · Translational Oncology · doi:10.1016/j.tranon.2021.101146 · Cited by 15
Brockmeier, U., Platzek, C., Schneider, K., Patak, P., Bernardini, A., Fandrey, J., & Metzen, E. (2011) · PLoS ONE · doi:10.1371/journal.pone.0019151 · Cited by 14
“It has been reported, however, that elevated levels of succinate and fumarate in succinate dehydrogenase or fumarate hydratase deficient tumors inhibit HIF hydroxylases and, as a consequence, activate HIF [6,7].”
Background15 YEARS OF PARAGANGLIOMA: Metabolism and pheochromocytoma/paraganglioma
Mannelli, M., Rapizzi, E., Fucci, R., Canu, L., Ercolino, T., Luconi, M., & Young, W. F. (2015) · Endocrine Related Cancer · doi:10.1530/erc-15-0215 · Cited by 15
Yang, J., Miao, D., Li, X., Zhao, C., Tan, D., Wu, S., Lu, F., Shi, J., Lv, Q., Ruan, H., et al. (2025) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2025.1664292 · Cited by 15
The return of metabolism: biochemistry and physiology of glycolysis
Grüning, N., Agostini, F., Caldana, C., Hartl, J., Heinemann, M., Keller, M. A., Krüsemann, J. L., Lamperti, C., Linster, C. L., Lindner, S. N., et al. (2025) · Biological reviews/Biological reviews of the Cambridge Philosophical Society · doi:10.1111/brv.70104 · Cited by 18
Hoekstra, M., Ridgeway, N. H., & Biggar, K. K. (2022) · The Journal of Biochemistry · doi:10.1093/jb/mvac081 · Cited by 13
Chromatin as a sensor of metabolic changes during early development
Pladevall‐Morera, D., & Żylicz, J. J. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.1014498 · Cited by 14
“On the contrary, pyruvate and the TCA cycle intermediates succinate and fumarate were found to inhibit PHDs and, hence, stabilize and increase the levels of HIF TFs (Selak et al., 2005; Virtue and Vidal-Puig, 2011; Wang et al., 2019).”
BackgroundGrimm, F., Asuaje, A., Jain, A., dos Santos, M. S., Kleinjung, J., Nunes, P. M., Gehrig, S. M., Fets, L., Darici, S., MacRae, J. I., et al. (2024) · The EMBO Journal · doi:10.1038/s44318-024-00065-w · Cited by 15
“Some oncometabolites can outcompete α KG binding to PHDs, leading to HIF stabilisation (Hewitson et al, 2007; Intlekofer et al, 2017; Koivunen et al, 2007; Selak et al, 2005), and this can be alleviated by exogenous α KG (Isaacs et al, 2005; MacKenzie et al, 2007; Tennant et al, 2009).”
Goretzki, A., Lin, Y., Zimmermann, J., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232012695 · Cited by 13
Oncometabolism: A Paradigm for the Metabolic Remodeling of the Failing Heart
Kuhn, A.-R., & van Bilsen, M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232213902 · Cited by 13
SDHB reduction promotes oral lichen planus by impairing mitochondrial respiratory function
Zhang, H., Xu, B., Liu, J., et al. (2022) · Annals of Translational Medicine · doi:10.21037/atm-22-5999 · Cited by 13
“An ATP Bioluminescence Assay Kit CLSII (Roche Applied Science, Mannheim, Germany) was employed for measuring total ATP in cells in line with specific protocols.”
InfluentialTakamori, H., Yamasaki, T., Kitadai, R., Minamishima, Y. A., & Nakamura, E. (2023) · Cancer Science · doi:10.1111/cas.15728 · Cited by 14
Hypoxia-adenosine axis as therapeutic targets for acute respiratory distress syndrome
Figarella, K., Kim, J., Ruan, W., Mills, T., Eltzschig, H. K., & Yuan, X. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1328565 · Cited by 15
Agitation by Suffocation: How Hypoxia Activates Innate Immunity via the Warburg Effect
Wen, H., & Ting, J. P. ‐. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.05.016 · Cited by 13
“Previous studies in can- Elsevier Inc. cer cells have shown that excessive cytosolic succinate suppresses the catalytic activity of PHD and thereby promotes accumulation of HIF-1a (Selak et al., 2005).”
BackgroundCañuelo, A., Martínez‐Romero, R., Martínez‐Lara, E., Sánchez-Alcázar, J. A., & Siles, E. (2011) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-011-1162-1 · Cited by 13
“Given that succinate is a coproduct of the reaction catalyzed by PHDs and that these enzymes are responsible for HIF-1a degradation, it has been proposed that the mitochondrial accumulation of succinate due to SDH downregulation results in the product inhibition of PHDs, which then leads to HIF-1a stabilization [37].”
BackgroundCharacterization of a Robust Enzymatic Assay for Inhibitors of 2-Oxoglutarate-Dependent Hydroxylases
Kanelakis, K. C., Palomino, H. L., Li, L., Wu, J., Yan, W., Rosen, M. D., Rizzolio, M., Trivedi, M. V., Morton, M. F., Yang, Y., et al. (2009) · SLAS DISCOVERY · doi:10.1177/1087057109333976 · Cited by 15
“additional reports have described the Kreb’s cycle intermediates as inhibitors of the pHd enzymes.(14,16) to rule out the possibility that the succinic acid produced in the enzymatic reaction inhibits pHd2181-417 activity, we tested the ability of exogenous succinic acid to inhibit the reaction.”
BackgroundPrecision Surgery for Pheochromocytomas and Paragangliomas
Wiseman, D., Lakis, M. E., & Nilubol, N. (2019) · Hormone and Metabolic Research · doi:10.1055/a-0926-3618 · Cited by 13
Genetically Encoded Tools for Research of Cell Signaling and Metabolism under Brain Hypoxia
Kostyuk, A. I., Kokova, A. D., Podgorny, O. V., Kelmanson, I. V., Fetisova, E. S., Belousov, V. V., & Bilan, D. S. (2020) · Antioxidants · doi:10.3390/antiox9060516 · Cited by 13
“It is well known that mutations in succinate dehydrogenase are linked to elevated levels of its substrate, which is also a potent inhibitor of prolyl hydroxylation [131].”
BackgroundBrookes, P. S., Freeman, R. S., & Barone, M. C. (2006) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2006.03.019 · Cited by 13
Effects of Dietary Energy Restriction on Gene Regulation in Mammary Epithelial Cells
Zhu, Z., Jiang, W., McGinley, J. N., Price, J., Gao, B., & Thompson, H. J. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-2834 · Cited by 13
Satoh, N., Yokoyama, C., Itamura, N., Miyajima-Nakano, Y., & Hisatomi, H. (2014) · Oncology Letters · doi:10.3892/ol.2014.2699 · Cited by 13
“SDHC is involved in the TCA cycle and electron transport chain (3-5).”
Costa, B., Dettori, D., Lorenzato, A., Bardella, C., Coltella, N., Martino, C., Cammarata, C., Carmeliet, P., Olivero, M., & Renzo, M. F. D. (2010) · The FASEB Journal · doi:10.1096/fj.09-146928 · Cited by 13
“This is in agreement with the lack of ROS accumulation reported in fibroblasts accumulating either succinate or succinate and fumarate due to mitochondrial tumor suppressor homozygous inactivation (29, 30).”
BackgroundIgaz, P., Wiener, Z., Szabó, P. M., Falus, A., Gaillard, R. C., Horányi, J., Rácz, K., & Tulassay, Z. (2006) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2006.06.011 · Cited by 13
Mitochondria at the Heart of Sepsis: Mechanisms, Metabolism, and Sex Differences
Yap, J. Q., Nikouee, A., Lau, J. E., Walsh, G., & Zang, Q. S. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26094211 · Cited by 15
“Succinate inhibits the activity of prolyl hydroxylase domain-containing enzymes (PHD), leading to the stabilization and activation of the transcription factor HIF-1 α [45].”
Effect of cadmium in the gonads of mussel (Mytilus coruscus): an ionomics and proteomics study
Meng, C., Wang, K., Zhang, X., & Zhu, X. (2023) · Environmental Science and Pollution Research · doi:10.1007/s11356-023-27208-6 · Cited by 11
“Tumorigenesis caused by SDH deficiency is said to be associated with the deleterious effects of supraphysiological levels of succinate (Selak et al. 2005; Xiao et al. 2012).”
BackgroundJiang, X. W., Peng, J., Xie, Y., Xu, Y., Liu, Q., Cheng, C., Yan, P., Xu, S., Wang, Y., Zhang, L., et al. (2023) · Cell Death and Differentiation · doi:10.1038/s41418-023-01186-1 · Cited by 12
Cui, H., Zhu, B. T., Li, H., Meng, Y., Cai, M., Wang, H., Yuan, M., Zhong, X., Wang, B., Shan, H., et al. (2023) · Biochemical Pharmacology · doi:10.1016/j.bcp.2023.115950 · Cited by 13
Hypoxia makes EZH2 inhibitor not easy—advances of crosstalk between HIF and EZH2
Huang, Z., Tang, Y., Zhang, J., Huang, J., Cheng, R., Guo, Y., Kleer, C. G., Wang, Y., & Xue, L. (2024) · Life Metabolism · doi:10.1093/lifemeta/loae017 · Cited by 12
“On the other side, various TCA cycle intermediates, such as succinate [49] and ROS [50], can enhance the HIF-1 α /EZH2 axis.”
BackgroundTargeting EGLN2/PHD1 protects motor neurons and normalizes the astrocytic interferon response
Germeys, C., Vandoorne, T., Davie, K., Poovathingal, S. K., Heeren, K., Vermeire, W., Nami, F., Moisse, M., Quaegebeur, A., Sierksma, A. S. R., et al. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114719 · Cited by 12
Todisco, S., Iacobazzi, D., Santarsiero, A., Convertini, P., & Infantino, V. (2025) · Molecular Metabolism · doi:10.1016/j.molmet.2025.102233 · Cited by 15
Sun, Y., Li, J., Zhao, X., Xu, J., Shi, M., & Liu, P. (2019) · PubMed Central · Cited by 13
Cho, S., Song, N., Choi, J., & Shin, A. (2020) · Cancers · doi:10.3390/cancers12102939 · Cited by 13
“Results from an in vitro study have suggested that the accumulation of succinate leads to the oncogenic signal via HIF-1α regulatory pathway [12].”
BackgroundMitochondrial Tumor Suppressors—The Energetic Enemies of Tumor Progression
Jakoubě, P., Cutano, V., González-Morena, J. M., & Keckesova, Z. (2021) · Cancer Research · doi:10.1158/0008-5472.can-21-0518 · Cited by 13
“This process stabilizes HIF1a what leads to expression of genes involved in the promotion of angiogenesis, metastasis, and metabolism, contributing to more aggressive tumor phenotypes (164).”
BackgroundMicroRNA‐16‐5p exacerbates sepsis by upregulating aerobic glycolysis via SIRT3‐SDHA axis
He, Y., Huang, B., Yang, Y., Song, W., Fan, Y., Zhang, L., & Liu, G. (2022) · Cell Biology International · doi:10.1002/cbin.11908 · Cited by 12
“SDH is deacetylated and activated by SIRT3 in mouse liver and adipose tissue (Cimen et al., 2010; Finley et al., 2011), while accumulation of succinate results in elevated glycolysis (Selak et al., 2005), implying that SIRT3 may target SDHA to regulate glycolysis during sepsis.”
BackgroundInfluentialPsurski, M. (2014) · Journal of Cancer Science & Therapy · doi:10.4172/1948-5956.1000249 · Cited by 10
A study on the involvement of GABA-transaminase in MCT induced pulmonary hypertension
Lingeshwar, P., Kaur, G., Singh, N., et al. (2015) · Pulmonary Pharmacology & Therapeutics · doi:10.1016/j.pupt.2015.11.002 · Cited by 12
Yamamoto, M., Tanaka, H., Toki, Y., Hatayama, M., Ito, S., Addo, L., Shindo, M., Sasaki, K., Ikuta, K., Ohtake, T., et al. (2016) · International Journal of Hematology · doi:10.1007/s12185-016-2054-7 · Cited by 12
Hypoxic behavior in cells under controlled microfluidic environment
Morshed, A. Z., & Dutta, P. (2017) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2017.01.017 · Cited by 12
Metabolic Enzymes in Sarcomagenesis: Progress Toward Biology and Therapy
Li, L., Eid, J. E., Paz, A. C., & Trent, J. C. (2017) · BioDrugs · doi:10.1007/s40259-017-0237-2 · Cited by 12
Pekny, J. E., Smith, P. B. W., & Marden, J. H. (2018) · Journal of Experimental Biology · doi:10.1242/jeb.171009 · Cited by 15
“During development and physiological adjustments throughout life, oxygen supply to the tissues is regulated by the hypoxia-inducible factor (HIF) pathway, a feedback loop that uses accumulation of succinate as a signal of insufficient oxygen supply (Pollard et al., 2005; Selak et al., 2005).”
Background3-Hydroxypyruvate Destabilizes Hypoxia Inducible Factor and Induces Angiostasis
Singh, C., Sharma, A. K., Hoppe, G., Song, W., Bolok, Y., & Sears, J. E. (2018) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.18-24120 · Cited by 13
“And in tumors with succinate dehydrogenase deficiency, succinate accumulation is considered a HIF stabilizing environment because it is a product of trans-4-prolylhydroxyation of HIF and should therefore inhibit the forward reaction associated with enzyme activity.(29,30) Hyperoxia downregulates and HIF stabilization…”
BackgroundMarden, J. H., Langford, E. A., Robertson, M. A., & Fescemyer, H. W. (2020) · Evolution · doi:10.1111/evo.14095 · Cited by 11
“2C) regardless of tracheal oxygen delivery, similar to the way human Sdhd mutations cause succinate accumulation, chronic HIF activation (pseudohypoxia), and development of vascularized tumors (Selak et al. 2005; Lendvai et al. 2014).”
BackgroundNew cancer targets emerging from studies of the Von Hippel‐Lindau tumor suppressor protein
Kaelin, W. G. (2010) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2010.05781.x · Cited by 12
Hypoxia Signaling and Circadian Disruption in and by Pheochromocytoma
Tabebi, M., Söderkvist, P., & Jensen, L. D. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00612 · Cited by 12
Cedó, L., Madeira, A., & Caro, P. (2025) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2025.10.007 · Cited by 14
The Molecular Role of HIF1α Is Elucidated in Chronic Myeloid Leukemia
Singh, V. K., Singh, R., Kushwaha, R., Verma, S. P., Tripathi, A. K., & Mahdi, A. A. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.912942 · Cited by 11
“These metabolites are involved in promoting the accumulation and stabilization of HIF1a in the presence of oxygen and create a pseudohypoxic environment through inhibition of the PHD domain (29, 32).”
BackgroundProvenzano, A., Chetta, M., Filpo, G. D., Cantini, G., Barbera, A. L., Nesi, G., Santi, R., Martinelli, S., Rapizzi, E., Luconi, M., et al. (2022) · Medicina · doi:10.3390/medicina58081113 · Cited by 11
The role of immunomodulatory metabolites in shaping the inflammatory response of macrophages
Park, D., Lim, G., Yoon, S., Yi, H., & Choi, D. W. (2022) · BMB Reports · doi:10.5483/bmbrep.2022.55.11.128 · Cited by 12
Gong, K., Huang, Y., Zheng, Y., Zhu, Y., Hao, W., & Shi, K. (2024) · Discover Oncology · doi:10.1007/s12672-024-01013-0 · Cited by 12
Kawahara, I., Yoshino, H., Fukumoto, W., Arima, J., Saito, S., Li, G., Fukuda, I., Mitsuke, A., Sakaguchi, T., Inoguchi, S., et al. (2024) · Molecular Oncology · doi:10.1002/1878-0261.13684 · Cited by 13
The Role of the Microbiome and of Radiotherapy-Derived Metabolites in Breast Cancer
Herrera‐Quintana, L., Vázquez‐Lorente, H., Silva, R. C. M. C., Arancibia, J. E. O., Reyes-Amigo, T., Pires, B. R. B., & Plaza‐Díaz, J. (2024) · Cancers · doi:10.3390/cancers16213671 · Cited by 11
Analysis of SDHD promoter mutations in various types of melanoma
Scholz, S. L., Horn, S., Murali, R., Möller, I., Sucker, A., Sondermann, W., Stiller, M., Schilling, B., Livingstone, E., Zimmer, L., et al. (2015) · OncoTarget · doi:10.18632/oncotarget.4665 · Cited by 12
Al‐Obaidy, K. I., Alruwaii, Z. I., Williamson, S. R., & Liang Cheng, C. (2022) · Histopathology · doi:10.1111/his.14641 · Cited by 11
“The pathogenic role of SDH mutation in tumorigenesis is not fully understood; however, the accumulation of intracellular succinate is thought to be related to an oncogenic effect caused by PHD enzyme inhibition and genome-wide hypermethylation (Figure 2).(101,102) As such, there are no evidence-based treatment/guideli…”
BackgroundGoretzki, A., Zimmermann, J., Lin, Y., & Schülke, S. (2022) · Frontiers in Allergy · doi:10.3389/falgy.2022.825931 · Cited by 13
“Here, succinate acted as a cell-intrinsic danger signal driving pro-inflammatory IL-1β production via stabilization of HIF-1α (termed “pseudohypoxia,” Figure 2) (22, 26).”
BackgroundShikonin impairs mitochondrial activity to selectively target leukemia cells
Roma, A., Tcheng, M., Ahmed, N., Walker, S., Jayanth, P., Minden, M. D., Reisz, J. A., D’Alessandro, A., Rohlena, J., & Spagnuolo, P. A. (2022) · Phytomedicine Plus · doi:10.1016/j.phyplu.2022.100300 · Cited by 11
Crosstalk of Epigenetic and Metabolic Signaling Underpinning Glioblastoma Pathogenesis
Markouli, M., Strepkos, D., Papavassiliou, K. A., Papavassiliou, A. G., & Piperi, C. (2022) · Cancers · doi:10.3390/cancers14112655 · Cited by 12
“Other mutated TCA cycle enzymes include fumarate hydratase [106] and succinate dehydrogenase, resulting in succinate and fumarate accumulation, which inhibit TET enzymes as well as the degradation of HIF, promoting the Warburg effect and enhancing the methylation of the entire genome, respectively [107,108] (Figure 3).”
BackgroundBaysal, B. E., Alahmari, A. A., Rodrick, T. C., Tabaczynski, D., Curtin, L. I., Seshadri, M., Jones, D. R., & Sexton, S. (2022) · JCI Insight · doi:10.1172/jci.insight.158737 · Cited by 12
“Increased succinate relative to oxoglutarate inhibits α-ketoglutarate–dependent enzymes, including HIF prolyl hydroxylases (68), Jumonji domain histone demethylases (69), and TET family of 5-methyldeoxycytosine hydroxylases (70), contributing to pseudohypoxia and hypermethylation in PGL tumors.”
BackgroundRoy, M. K., Wilkerson, R. B., Alexander, K., Nokoff, N., Cree‐Green, M., & D’Alessandro, A. (2022) · Blood Advances · doi:10.1182/bloodadvances.2022008061 · Cited by 11
“Decreases in all carboxylic acids after testosterone treatment were accompanied by increases in 2-oxoglutarate, a negative regulator of hypoxia-inducible factor 1 alpha (HIF1α) by the mechanism of prolyl hydroxylase– dependent posttranslational modification of HIF1α.20,21 This observation is suggestive of potential co…”
BackgroundFumarate Hydratase Variants and Their Association With Paraganglioma/Pheochromocytoma
Zavoshi, S., Lu, E., Boutros, P. C., Zhang, L., Harari, A., Hatchell, K. E., Nielsen, S. M., Esplin, E. D., Ouyang, K., Nykamp, K., et al. (2023) · Urology · doi:10.1016/j.urology.2022.11.053 · Cited by 11
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Pheochromocytoma/Paraganglioma: A Poster Child for Cancer Metabolism
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“HIF dimer even in the presence of abundant oxygen, a condition known as pseudohypoxia (69, 73).”
BackgroundNovel potential causative genes in carotid paragangliomas
Snezhkina, A. V., Lukyanova, E., Zaretsky, A. R., Kalinin, D. V., Pokrovsky, A. V., Golovyuk, A. L., Krasnov, G. S., Fedorova, M., Pudova, E. A., Kharitonov, S., et al. (2019) · BMC Medical Genetics · doi:10.1186/s12881-019-0770-6 · Cited by 11
“The mutated ARNT (HIF1B) gene, which encodes an aryl hydrocarbon nuclear translocator, was identified in CPGLs [16].”
BackgroundInfluentialMaster regulator analysis of paragangliomas carrying SDHx, VHL, or MAML3 genetic alterations
Smestad, J. A., & Maher, L. J., III (2019) · BMC Cancer · doi:10.1186/s12885-019-5813-z · Cited by 11
Vitamin B3-Based Biologically Active Compounds as Inhibitors of Human Cholinesterases
Zandona, A., Lihtar, G., Maraković, N., Miš, K., Bušić, V., Gašo-Sokač, D., Pirkmajer, S., & Katalinić, M. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21218088 · Cited by 12
“The inhibition of succinate dehydrogenase increases succinate levels and suppresses HIF-1α proteolysis [66].”
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“Mutations in SDH or fumarase in cancer lead to stabilization of hypoxia-inducible factor 1-alpha (HIF1α) and thus activate a pseudo-hypoxic response (Isaacs et al., 2005; Selak et al., 2005).”
BackgroundGermline DLST Variants Promote Epigenetic Modifications in Pheochromocytoma-Paraganglioma
Buffet, A., Zhang, J., Rebel, H. G., Corssmit, E. P. M., Jansen, J. C., Hensen, E. F., Bovée, J. V. M. G., Morini, A., Gimenez‐Roqueplo, A., Hes, F. J., et al. (2020) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgaa819 · Cited by 11
SIRT7–SREBP1 restrains cancer cell metabolic reprogramming by upregulating IDH1
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The Crucial Roles of Intermediate Metabolites in Cancer
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Whole blood genome-wide expression profiling and network analysis suggest MELAS master regulators
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The Metabolic Basis of Kidney Cancer
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Mitochondrial bioenergetics of breast cancer
Singh, T., Sharma, K., Jena, L., Kaur, P., Singh, S., & Munshi, A. (2024) · Mitochondrion · doi:10.1016/j.mito.2024.101951 · Cited by 11
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Review: Warburg effect and renal cancer caused by errs in fumarate hydratase encoding gene.
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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.
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