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
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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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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)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesThe 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- 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
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes? Based: unclearIt 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesThe 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably 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
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably 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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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.
Di3 microscopy panel is described both with and without pVHL
MinorThe Figure 6A legend identifies panel v as the Di3 condition without pVHL. The results text instead describes the Di3 and Di4 comparisons in panels iv-vi as experiments cotransfected with HA-tagged pVHL, so the Di3 condition is inconsistent between the two descriptions.
“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).”
“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
Flagged first, then by citations
2 of the 47 references couldn’t be matched to a known paper.
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
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Extracellular matrix and HIF‐1 signaling: The role of prolidase
Surażyński, A., Donald, S. P., Cooper, S. K., Whiteside, M. A., Salnikow, K., Liu, Y., & Phang, J. M. (2007) · International Journal of Cancer · doi:10.1002/ijc.23263 · Cited by 113
“In the context of cancer biology, target genes of HIF-1 are upregulated with hypoxic and nutrient stress and mediate angiogenesis, glycolysis, metastasis and survival.3 HIF-1 signaling responds to decreased oxygen tension, because oxygen is necessary for prolyl hydroxylation and degradation of HIF-1a;1–3 hypoxia, ther…”
BackgroundInfluentialNi, Y., He, X., Chen, J., Moline, J., Mester, J. L., Orloff, M. S., Ringel, M. D., & Eng, C. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr459 · Cited by 120
“the prolyl-hydroxylase enzyme and contributes to stabilization of HIF1a in turn promoting transcription of genes containing hypoxic response elements believed to promote cancer (16).”
BackgroundSarrazy, V., Viaud, M., Westerterp, M., Ivanov, S., Giorgetti‐Peraldi, S., Guinamard, R., Gautier, E. L., Thorp, E. B., Vivo, D. C. D., & Yvan‐Charvet, L. (2016) · Circulation Research · doi:10.1161/circresaha.115.307599 · Cited by 123
“The absence of succinate accumulation in ApoE BM cells could also contribute to the lack of HIF-1α activation in these cells.(50) Consistent with these observations, we did not observe modulation of the oxygenation status of ApoE LTHSCs in chronic hypercholesterolemia, and HIF-1α deficiency in WT or ApoE hematopoietic…”
Dogra, N., Kumar, A., & Mukhopadhyay, T. (2018) · Scientific Reports · doi:10.1038/s41598-018-30158-6 · Cited by 117
Na, U., Yu, W., Cox, J. E., Bricker, D. K., Brockmann, K., Rutter, J. P., Thummel, C. S., & Winge, D. R. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.05.014 · Cited by 114
“…from SDH deficiency is purportedly related to the deleterious effects of supraphysiological levels of succinate, which is a known inhibitor of a myriad of a-ketoglutarate (aKG)-dependent enzymes, including prolyl hydroxylases, histone, and DNA demethylases (Selak et al., 2005; Xiao et al., 2012).”
Disease-Causing SDHAF1 Mutations Impair Transfer of Fe-S Clusters to SDHB
Maio, N., Ghezzi, D., Verrigni, D., Rizza, T., Bertini, E., Martinelli, D., Zeviani, M., Singh, A., Carrozzo, R., & Rouault, T. A. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.12.005 · Cited by 116
“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript cells correlated with accumulation of succinate (Figure 7D), which promotes HIF stabilization (Selak et al., 2005).”
BackgroundInfluentialSTING regulates metabolic reprogramming in macrophages via HIF-1α during Brucella infection
Gomes, M. T. R., Guimarães, E. S., Marinho, F. V., Macedo, I., Aguiar, E. R. G. R., Barber, G. N., Moraes‐Vieira, P. M., Alves-Filho, J. C., & Oliveira, S. C. (2021) · PLoS Pathogens · doi:10.1371/journal.ppat.1009597 · Cited by 116
“Succinate promotes HIF-1α stabilization by inhibiting PHD activity [51].”
Matyakhina, L., Freedman, R. J., Bourdeau, I., Wei, M.-H., Stergiopoulos, S. G., Chidakel, A. R., Walther, M. M., Abu-Asab, M. S., Tsokos, M., Keil, M. F., et al. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-2377 · Cited by 114
Molecular Responses to Hypoxia-Inducible Factor 1α and Beyond
Brocato, J., Chervona, Y., & Costa, M. (2014) · Molecular Pharmacology · doi:10.1124/mol.113.089623 · Cited by 114
“Elevated levels of fumarate and succinate, in fumarate hydratase and succinate dehydrogenase–deficient tumors, were shown to inhibit all three PHDs, resulting in consequent stabilization/ upregulation of HIFa and their product genes (Isaacs et al., 2005; Selak et al., 2005).”
BackgroundThe Metabolic Basis of Immune Dysfunction Following Sepsis and Trauma
McBride, M. A., Owen, A. M., Stothers, C. L., Hernandez, A., Luan, L., Burelbach, K. R., Patil, T. K., Bohannon, J. K., Sherwood, E. R., & Patil, N. K. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01043 · Cited by 120
Michalak, K. P., & Michalak, A. Z. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1558263 · Cited by 148
Desideri, E., Vegliante, R., & Ciriolo, M. R. (2014) · Cancer Letters · doi:10.1016/j.canlet.2014.02.023 · Cited by 116
Endothelial cell metabolism: parallels and divergences with cancer cell metabolism
Verdegem, D., Moens, S., Stapor, P. C., & Carmeliet, P. (2014) · Cancer & Metabolism · doi:10.1186/2049-3002-2-19 · Cited by 117
“lases [105,106].”
Harada, H. (2016) · Journal of Radiation Research · doi:10.1093/jrr/rrw012 · Cited by 116
“reported that a deficiency in succinate dehydrogenase (SDH), which is often confirmed in some types of cancers, results in the accumulation of succinate in cells [29].”
BackgroundTargeting Cancer Metabolism - Revisiting the Warburg Effects
Tran, Q., Lee, H., Park, J., Kim, S., & Park, J. (2016) · Toxicological Research · doi:10.5487/tr.2016.32.3.177 · Cited by 116
“The enhancement of these HIF-target genes synergistically promotes the Warburg effect, allowing cancer cells to gain growth advantages (29,34,35).”
BackgroundRevisiting the Warburg Effect with Focus on Lactate
Kocianova, E., Piatrikova, V., & Golias, T. (2022) · Cancers · doi:10.3390/cancers14246028 · Cited by 124
The good, the bad and the ugly in oxygen-sensing: ROS, cytochromes and prolyl-hydroxylases
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“[94] Selak MA, Armour SM, MacKenzie ED, Boulahbel H, Watson DG, Mansfield KD, et al.”
BackgroundThe magic of the hypoxia-signaling cascade
Benizri, E. I., Ginouvès, A., & Berra, E. (2008) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-008-7472-0 · Cited by 112
Pillai, S., Gopalan, V., Smith, R. A., & Lam, A. K.-Y. (2016) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2016.01.022 · Cited by 113
“Inactivation of SDH complex causes accumulation of succinate and this inhibits EGLN/PHD enzyme activity, thereby leading to HIFstabilization and activation of HIF target genes resulting in the development of PCC/PGLs (Selak et al., 2005).”
BackgroundLi, Y., Zheng, J., Liu, J., Yang, J., Liu, Y., Wang, C., Ma, X., Liu, B., Xin, G.-Z., & Liu, L. (2016) · Frontiers in Immunology · doi:10.3389/fimmu.2016.00532 · Cited by 110
“Indeed, SDH inhibition induces succinate accumulation in tumor cells (29).”
BackgroundBiochemistry of proinflammatory macrophage activation
Nonnenmacher, Y., & Hiller, K. (2018) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-018-2784-1 · Cited by 112
“The LPS-induced stabilization of HIF-1α by cytosolic succinate [15] and mROS [23], even under normoxic conditions, pushes cells into a state termed pseudohypoxia [60].”
BackgroundInterplay Among Metabolism, Epigenetic Modifications, and Gene Expression in Cancer
Huo, M., Zhang, J., Huang, W., & Wang, Y. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.793428 · Cited by 117
“In renal cancer, the inactivating mutations of SDH or FH deficiency results in the subsequent accumulation of succinate or fumarate, respectively, thus, the inhibition of hypoxia-inducible factor (HIF) prolyl hydroxylases (HPH), which protect the stabilization of HIF and promote angiogenesis by increasing α-KG intake…”
BackgroundThe tumor suppressor function of mitochondria: Translation into the clinics
Cuezva, J. M., Ortega, A. D., Willers, I. M., Sánchez-Cenizo, L., Aldea, M., & Sánchez‐Aragó, M. (2009) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2009.01.006 · Cited by 111
“2) [81,82].”
Pheochromocytomas: The (pseudo)-hypoxia hypothesis
Favier, J., & Gimenez‐Roqueplo, A. (2010) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2010.10.004 · Cited by 117
McKnight, S. L. (2010) · Science · doi:10.1126/science.1199908 · Cited by 108
Eckle, T. D. L. G., Kewley, E. M., Brodsky, K. S., Tak, E., Bonney, S. K., Gobel, M., Anderson, D. E., Glover, L. E., Riegel, A. K., Colgan, S. P., et al. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1100593 · Cited by 113
Porporato, P. E., Payen, V. L., Baselet, B., & Sonveaux, P. (2015) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-015-2100-2 · Cited by 115
Rivadeneira, D. B., Caino, M. C., Seo, J. H., Angelin, A., Wallace, D. C., Languino, L. R., & Altieri, D. C. (2015) · Science Signaling · doi:10.1126/scisignal.aab1624 · Cited by 114
“S1H), which mediates transcriptional responses to hypoxia (11).”
BackgroundZou, X., Ratti, B. A., O’Brien, J., Lautenschlager, S. O., Gius, D. R., Bonini, M. G., & Zhu, Y. (2017) · Journal of Bioenergetics and Biomembranes · doi:10.1007/s10863-017-9718-8 · Cited by 115
Li, L., Zhang, L., Zhang, X., Yan, Q., Minamishima, Y. A., Olumi, A. F., Mao, M., Bartz, S. R., & Kaelin, W. G. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.00282-07 · Cited by 111
“As expected, HIF protein levels were suppressed by wild-type pVHL but not by pVHL(1-115) under normoxic conditions (Fig.”
BackgroundInfluentialCytochrome c: the Achilles’ heel in apoptosis
Kulikov, A. V., Shilov, E. S., Mufazalov, I. A., Gogvadze, V. G., Nedospasov, S. A., & Zhivotovsky, B. (2011) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-011-0895-z · Cited by 110
“Interestingly, complex II was shown to have tumor suppressor activity by limiting the accumulation of succinate in the cells [69].”
BackgroundHallmarks of Pulmonary Hypertension: Mesenchymal and Inflammatory Cell Metabolic Reprogramming
D’Alessandro, A., Kasmi, K. C. E., Plecitá‐Hlavatá, L., Ježek, P., Li, M., Zhang, H., Gupte, S. A., & Stenmark, K. R. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7217 · Cited by 111
“Supraphysiological levels of succinate and fumarate can also replace a-ketoglutarate as a mock substrate for prolyl-hydroxylase, thereby preventing HIF1 hydroxylation and promoting its stabilization, thus enhancing the Warburg effect (97, 187).”
BackgroundThe human oxygen sensing machinery and its manipulation
Chowdhury, R., Hardy, A., & Schofield, C. J. (2008) · Chemical Society Reviews · doi:10.1039/b701676j · Cited by 115
Tricarboxylic acid cycle dysfunction as a cause of human diseases and tumor formation
Brière, J.-J., Favier, J., Gimenez‐Roqueplo, A., & Rustin, P. (2006) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00216.2006 · Cited by 112
“Four years after the seminal observation in 2001 of the putative implication of HIFs in a paraganglioma due to a mutation in the SDHD gene (23), it was recently shown that the high concentration of succinate accumulated in tumors (45), or in SDH-deficient cells (11) directly linked to the loss of SDH activity, was suf…”
BackgroundFliedner, S. M. J., Lehnert, H., & Pacák, K. (2010) · Seminars in Oncology · doi:10.1053/j.seminoncol.2010.10.017 · Cited by 110
Mitochondrial complex II, a novel target for anti-cancer agents
Kluckova, K., Bezawork-Geleta, A., Rohlena, J., Dong, L., & Neuzil, J. (2013) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2012.10.015 · Cited by 104
Succinate in the cancer–immune cycle
Jiang, S., & Yan, W. (2017) · Cancer Letters · doi:10.1016/j.canlet.2017.01.019 · Cited by 111
Wu, B., Luo, H., Zhou, X., Cheng, C., Lin, L., Liu, B., Liu, K., Li, P., & Yang, H. Q. (2017) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2017.06.011 · Cited by 108
Update on pediatric pheochromocytoma
Havekes, B., Romijn, J. A., Eisenhofer, G., Adams, K. T., & Pacák, K. (2008) · Pediatric Nephrology · doi:10.1007/s00467-008-0888-9 · Cited by 108
Illsley, N. P., Caniggia, I., & Zamudio, S. (2010) · The International Journal of Developmental Biology · doi:10.1387/ijdb.082798ni · Cited by 107
“Thus, under hypoxic conditions, increased HIF-1 results in the suppression of SDHB expression, leading to increased succinate concentrations which, in turn, stabilize the increased level of HIF-1 (MacKenzie et al., 2007; Selak et al., 2005).”
BackgroundDecoding microglial immunometabolism: a new frontier in Alzheimer's disease research
Jung, E. S., Choi, H., & Mook-Jung, I. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-025-00825-0 · Cited by 124
Tumors of the neural crest: Common themes in development and cancer
Maguire, L. H., Thomas, A. R., & Goldstein, A. M. (2014) · Developmental Dynamics · doi:10.1002/dvdy.24226 · Cited by 111
“Unbound HIFα escapes degradation, migrates into the nucleus, forms heterodimers with HIFβ, and induces the expression of genes involved in angiogenesis, ECM modification, cell proliferation and survival, and glucose metabolism (Selak et al., 2005).”
BackgroundInfluentialMolecular Pathways: Mitochondrial Reprogramming in Tumor Progression and Therapy
Caino, M. C., & Altieri, D. C. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-0460 · Cited by 105
“Accordingly, loss-of-functionmutations in oxidative phosphorylation genes produce apro-oncogenic, pseudo-hypoxic state (5), inactivation of tumor suppressors, for instance p53 (6), or activating mutations in the Ras oncogene (7) stimulates glycolysis at the expense of oxidative phosphorylation, and stabilization of HI…”
BackgroundThe Metabolic Alterations of Cancer Cells
Sciacovelli, M., Gaude, E., Hilvo, M., & Frezza, C. (2014) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/b978-0-12-416618-9.00001-7 · Cited by 108
Salminen, A., Haapasalo, A., Kauppinen, A., Kaarniranta, K., Soininen, H. S., & Hiltunen, M. O. (2015) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2015.05.001 · Cited by 107
“succinate and fumarate, and thus they can stimulate the expression of HIF-1a (Selak et al., 2005; Koivunen et al., 2007; Hewitson et al., 2007).”
BackgroundCoenzyme A fuels T cell anti-tumor immunity
Paul, M. S., Saibil, S. D., Han, S., Israni-Winger, K., Lien, S. C., Laister, R. C., Sayad, A., Penny, S. L., Amaria, R. N., Haydu, L. E., et al. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2021.11.010 · Cited by 109
Eyeing central neurons in vascular growth and reparative angiogenesis
Sapieha, P. S. (2012) · Blood · doi:10.1182/blood-2012-04-396846 · Cited by 106
Szeto, S. S. W., Reinke, S. N., Sykes, B. D., & Lemire, B. D. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m700601200 · Cited by 104
Metabolic dysregulation in monogenic disorders and cancer — finding method in madness
Erez, A., & DeBerardinis, R. J. (2015) · Nature Reviews Cancer · doi:10.1038/nrc3949 · Cited by 105
SDH-related pheochromocytoma and paraganglioma
Kantorovich, V., King, K. S., & Pacák, K. (2010) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2010.04.001 · Cited by 105
“There seems to be even more complex metabolic relationship between SDH and HIF pathways (24).”
BackgroundInfluentialHow metabolites modulate metabolic flux
Wegner, A., Meiser, J., Weindl, D., & Hiller, K. (2014) · Current Opinion in Biotechnology · doi:10.1016/j.copbio.2014.11.008 · Cited by 108
Vitamin D endocrinology on the cross-road between immunity and metabolism
Vanherwegen, A.-S., Gysemans, C. A., & Mathieu, C. (2017) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2017.04.018 · Cited by 107
SIRT5-mediated SDHA desuccinylation promotes clear cell renal cell carcinoma tumorigenesis
Ma, Y., Qi, Y., Wang, L., Zheng, Z., Zhang, Y., & Zheng, J. (2019) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2019.01.030 · Cited by 105
Gasparre, G., Kurelac, I., Capristo, M., Iommarini, L., Ghelli, A. M., Ceccarelli, C., Nicoletti, G., Nanni, P., Giovanni, C. D., Scotlandi, K., et al. (2011) · Cancer Research · doi:10.1158/0008-5472.can-11-1042 · Cited by 102
“HIF1a is considered to be one of the master regulators of the metabolic adaptation needed by cancer cells to progress to malignancy (7, 8, 32).”
BackgroundMetabolic regulation of hematopoietic stem cell commitment and erythroid differentiation
Oburoglu, L., Romano, M., Taylor, N. N., & Kinet, S. (2016) · Current Opinion in Hematology · doi:10.1097/moh.0000000000000234 · Cited by 110
Cancer Metabolism: Fueling More than Just Growth
Lee, N., & Kim, D. (2016) · Molecules and Cells · doi:10.14348/molcells.2016.0310 · Cited by 102
“The activation of a HIF response is observed in SDH- or FD-deficient cancer cells, which could be explained by the allosteric suppression of PHDs by accumulated succinate or fumarate (Isaacs et al., 2005; Selak et al., 2005).”
BackgroundTCA Cycle Rewiring as Emerging Metabolic Signature of Hepatocellular Carcinoma
Todisco, S., Convertini, P., Iacobazzi, V., & Infantino, V. (2019) · Cancers · doi:10.3390/cancers12010068 · Cited by 105
“Increased levels of succinate activate HIF-1 which in turn up-regulates metabolic genes switching to the Warburg effect [26].”
BackgroundIommarini, L., Kurelac, I., Capristo, M., Calvaruso, M. A., Giorgio, V., Bergamini, C., Ghelli, A. M., Nanni, P., Giovanni, C. D., Carelli, V., et al. (2013) · Human Molecular Genetics · doi:10.1093/hmg/ddt533 · Cited by 108
Hypoxia-Inducible Factor and Its Role in the Management of Anemia in Chronic Kidney Disease
Kaplan, J., Sharma, N., & Dikdan, S. J. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19020389 · Cited by 108
“HIF-2α is the most important isoform in the response to anemia, supported by the recent observation that a mutation in the HIF-2α gene, which compromises binding of HIF-2α to PHD2 and VHL, is associated with erythrocytosis (Table 1) [26].”
BackgroundTET-Mediated Hypermethylation Primes SDH-Deficient Cells for HIF2α-Driven Mesenchymal Transition
Morin, A., Goncalves, J., Moog, S., Castro‐Vega, L. J., Job, S., Buffet, A., Fontenille, M., Woszczyk, J., Gimenez‐Roqueplo, A., Letouzé, É., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.03.022 · Cited by 110
Cancer cell metabolism and the modulating effects of nitric oxide
Chang, C.-F., Diers, A. R., & Hogg, N. (2014) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2014.11.012 · Cited by 103
The role of HIF prolyl hydroxylases in tumour growth
Jokilehto, T., & Jaakkola, P. (2010) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2010.01030.x · Cited by 104
“The glucose metabolites pyruvate, oxaloacetate, citrate, isocitrate, malate and fumarate all have been reported to inhibit PHDs by binding to the 2-oxoglutarate sites of the enzymes [67–72].”
BackgroundAltered glucose metabolism in childhood pre-B acute lymphoblastic leukaemia
Boag, J. M., Beesley, A. H., Firth, M. J., Freitas, J. R., Ford, J., Hoffmann, K., Cummings, A. J., de Klerk, N. H., & Kees, U. R. (2006) · Leukemia · doi:10.1038/sj.leu.2404365 · Cited by 103
Mitochondrial Fission and Fusion in Tumor Progression to Metastasis
Boulton, D. P., & Caino, M. C. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.849962 · Cited by 108
Applications of metabolomics in cancer research
Styczynski, M. P., & Vermeersch, K. A. (2013) · Journal of Carcinogenesis · doi:10.4103/1477-3163.113622 · Cited by 107
Hoekstra, A. S., de Graaff, M. A., Briaire-de Bruijn, I. H., Ras, C., Seifar, R. M., van Minderhout, I., Cornelisse, C. J., Hogendoorn, P. C. W., Breuning, M. H., Suijker, J., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.6091 · Cited by 99
“Inactivation of SDH and FH leads to accumulation of the respective substrates succinate and fumarate, which inhibit α-ketoglutarate (αKG) dependent HIF prolyl hydroxylases, leading to HIF activation [12, 13].”
BackgroundLéveillard, T., Philp, N. J., & Sennlaub, F. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20030762 · Cited by 103
“Succinate, in turn, is transported to the cytosol via the mitochondrial dicarboxylate carrier (SCL2A10), where it leads to the accumulation of hypoxia-inducible factor 1 (HIF1A) by inhibiting prolyl-hydroxylases (PHDs) and thus preventing HIF1A hydroxylation and degradation [92] (Figure 2•>••).”
BackgroundInfluentialSalminen, A., Kauppinen, A., & Kaarniranta, K. (2015) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-015-1978-z · Cited by 99
Lemarié, A., Laurence Therese, H. U. C., Pazarentzos, E., Mahul‐Mellier, A., & Grimm, S. (2010) · Cell Death and Differentiation · doi:10.1038/cdd.2010.93 · Cited by 98
Cells Silenced for SDHB Expression Display Characteristic Features of the Tumor Phenotype
Cervera, A. M., Apostolova, N., Crespo, F. L., Mata, M., & McCreath, K. J. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-5580 · Cited by 102
“Hep3B cells were incubated with culture medium containing 25 mmol/L dimethyl succinate (DMS) for 48 h ( 17 ), and total RNA was extracted for RT-PCR analysis.”
BackgroundMethodResultInfluentialHypoxia-inducible factors regulate T cell metabolism and function
Phan, A. T., & Goldrath, A. W. (2015) · Molecular Immunology · doi:10.1016/j.molimm.2015.08.004 · Cited by 103
Masgras, I., Ciscato, F., Brunati, A. M., Tibaldi, E. V., Indraccolo, S., Curtarello, M., Chiara, F., Cannino, G., Papaleo, E., Lambrughi, M., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2016.12.056 · Cited by 100
Commitment to Aerobic Glycolysis Sustains Immunosuppression of Human Mesenchymal Stem Cells
Liu, Y., Yuan, X., Munoz, N. M., Logan, T. M., & Ma, T. (2018) · Stem Cells Translational Medicine · doi:10.1002/sctm.18-0070 · Cited by 101
Hypoxia-mediated drug resistance in breast cancers
McAleese, C. E., Choudhury, C., Butcher, N. J., & Minchin, R. F. (2020) · Cancer Letters · doi:10.1016/j.canlet.2020.11.045 · Cited by 99
Why succinate? Physiological regulation by a mitochondrial coenzyme Q sentinel
Murphy, M. P., & Chouchani, E. T. (2022) · Nature Chemical Biology · doi:10.1038/s41589-022-01004-8 · Cited by 105
Cancer-derived extracellular succinate: a driver of cancer metastasis
Kuo, C.-C., Wu, J.-Y., & Wu, K. K. (2022) · Journal of Biomedical Science · doi:10.1186/s12929-022-00878-z · Cited by 107
Pheochromocytomas and secreting paragangliomas
Plouin, P., & Gimenez‐Roqueplo, A. (2006) · Orphanet Journal of Rare Diseases · doi:10.1186/1750-1172-1-49 · Cited by 96
“When SDH is inhibited, the accumulation of succinate seems to inhibit the prolyl-hydroxylation of HIF and induce, as in VHL disease, an inappropriate stabilization of HIF [13].”
BackgroundMitochondrial DNA mutations in ageing and cancer
Smith, A. L. M., Whitehall, J. C., & Greaves, L. C. (2022) · Molecular Oncology · doi:10.1002/1878-0261.13291 · Cited by 105
Molecular techniques and genetic alterations in head and neck cancer
Ha, P. K., Chang, S. S., Glazer, C. A., Califano, J. A., & Sidransky, D. (2008) · Oral Oncology · doi:10.1016/j.oraloncology.2008.05.015 · Cited by 96
“A more direct mechanistic link between cancer formation and mitochondria involve the accumulation of succinate (part of the tricarboxylic acid cycle), which inhibits the degradation if hypoxia-inducible factor(HIF)-1alpha, an angiogenic factor activated by tumor hypoxia.(64) Direct sequence analysis of HNSCC samples s…”
Succinate dehydrogenase deficiency in human
Brière, J.-J., Favier, J., Ghouzzi, V. E., Djouadi, F., Bénit, P., Gimenez‐Roqueplo, A., & Rustin, P. (2005) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-005-5237-6 · Cited by 95
The genetics of paragangliomas: a review
Martin, T., Irving, R. M., & Maher, E. R. (2007) · Clinical Otolaryngology · doi:10.1111/j.1365-2273.2007.01378.x · Cited by 95
Mitochondria as targets for cancer therapy
Ralph, S. J., & Neužil, J. (2009) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.200800044 · Cited by 98
Mitochondria control acute and chronic responses to hypoxia
McElroy, G. S., & Chandel, N. S. (2017) · Experimental Cell Research · doi:10.1016/j.yexcr.2017.03.034 · Cited by 100
Fibrometabolism—An emerging therapeutic frontier in pulmonary fibrosis
Selvarajah, B., Azuelos, I., Anastasiou, D., & Chambers, R. C. (2021) · Science Signaling · doi:10.1126/scisignal.aay1027 · Cited by 94
“In normoxia, succinate stabilizes the master regulator of hypoxia, HIF1, by inhibiting the prolyl hydroxylases responsible for its degradation (93).”
BackgroundRole of Intestinal HIF-2α in Health and Disease
Ramakrishnan, S. K., & Shah, Y. M. (2015) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021115-105202 · Cited by 100
“Increased succinate levels inhibit prolyl hydroxylases and stabilize HIF protein expression in inflamed tissues (31).”
Fumarate Hydratase Loss Causes Combined Respiratory Chain Defects
Tyrakis, P. A., Yurkovich, M. E., Sciacovelli, M., Papachristou, E. K., Bridges, H. R., Gaude, E., Schreiner, A., D’Santos, C. S., Hirst, J., Hernandez-Fernaud, J. R., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.09.092 · Cited by 96
Specific Inhibition of the NLRP3 Inflammasome as an Antiinflammatory Strategy in Cystic Fibrosis
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Primary Cilium in Cancer Hallmarks
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In vivo genetic dissection of tumor growth and the Warburg effect
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Mitochondrial fumarate reductase as a target of chemotherapy: From parasites to cancer cells
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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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