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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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Cited by
Sorted by citations
Items 1,001–1,100 of 2,106
Mao, H., Yang, A., Zhao, Y., Lei, L., & Li, H. (2020) · Stem Cells International · doi:10.1155/2020/2016809 · Cited by 35
“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 [19].”
BackgroundMethodInfluentialCasey, R. T., Neumann, H. P. H., & Maher, E. R. (2020) · Human Molecular Genetics · doi:10.1093/hmg/ddaa201 · Cited by 36
Vohwinkel, C. U., Coit, E. J., Burns, N., Elajaili, H. B., Hernández-Saavedra, D., Yuan, X., Eckle, T. D. L. G., Nozik‐Grayck, E., Tuder, R. M., & Eltzschig, H. K. (2021) · The FASEB Journal · doi:10.1096/fj.202002778r · Cited by 35
Germline SUCLG2 Variants in Patients with Pheochromocytoma and Paraganglioma.
Vanova, K. H., Pang, Y., Krobova, L., Kraus, M., Nahacka, Z., Boukalová, Š., Pack, S., Zobalova, R., Zhu, J., Huynh, T., et al. (2021) · Journal of the National Cancer Institute · doi:10.1093/jnci/djab158 · Cited by 32
“Second, the other product of the enzyme, succinate, is an oncometabolite (20) and a substrate for CII that is linked to PPGL.”
BackgroundMechanisms of acute oxygen sensing by the carotid body: Lessons from genetically modified animals
Ortega‐Sáenz, P., Pascual, A., Piruat, J. I., & López‐Barneo, J. (2007) · Respiratory Physiology & Neurobiology · doi:10.1016/j.resp.2007.02.009 · Cited by 35
Tumor metabolism: new opportunities for cancer therapy
Mérida, I., & Ávila‐Flores, A. (2006) · Clinical & Translational Oncology · doi:10.1007/s12094-006-0117-6 · Cited by 35
Understanding hypoxia signalling in cells – a new therapeutic opportunity?
Ratcliffe, P. J. (2006) · Clinical Medicine · doi:10.7861/clinmedicine.6-6-573 · Cited by 33
Mitochondrial metabolism in macrophages
Nassef, M. Z., Hanke, J. E., & Hiller, K. (2021) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00126.2021 · Cited by 32
Contribution of fatty acid oxidation to the pathogenesis of pulmonary hypertension
Lee, M. H., Sanders, L., Kumar, R., Hernández-Saavedra, D., Yun, X., Ford, J. A., Perez, M. J., Mickael, C. S., Gandjeva, A., Koyanagi, D. E., et al. (2022) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00039.2022 · Cited by 33
Nannini, M., Astolfi, A., Paterini, P., Urbini, M., Santini, D., Catena, F., Indio, V., Casadio, R., Pinna, A. D., Biasco, G., et al. (2012) · Future Oncology · doi:10.2217/fon.12.170 · Cited by 34
Lin, S., Yang, Z., Liu, H., & Cai, Z. (2011) · Molecular BioSystems · doi:10.1039/c1mb05057e · Cited by 34
Urayama, S. (2015) · World Journal of Gastroenterology · doi:10.3748/wjg.v21.i6.1707 · Cited by 36
Plasma proteomic study of acute mountain sickness susceptible and resistant individuals
Lu, H., Wang, R., Li, W., Xie, H., Wang, C., Hao, Y., Sun, Y., & Jia, Z. (2018) · Scientific Reports · doi:10.1038/s41598-018-19818-9 · Cited by 35
Kobliakov, V. A. (2019) · Biochemistry (Moscow) · doi:10.1134/s0006297919100018 · Cited by 34
When S -Nitrosylation Gets to Mitochondria: From Signaling to Age-Related Diseases
Montagna, C., Cirotti, C., Rizza, S., & Filomeni, G. (2020) · Antioxidants and Redox Signaling · doi:10.1089/ars.2019.7872 · Cited by 35
“Both these metabolites have been reported to inhibit the hydroxylation (and, in turn, compromise the stability of) hypoxia inducible factor-1 a (HIF1 a ) (147), which is catalyzed by the prolyl-hydroxylase (PHD) family members (82).”
Innate immune training and metabolic reprogramming in primary monocytes of broiler and laying hens
Verwoolde, M. B., van den Biggelaar, R. H. G. A., Reilingh, G. D. V., Arts, J. A. J., van Baal, J., Lammers, A., & Jansen, C. A. (2020) · Developmental & Comparative Immunology · doi:10.1016/j.dci.2020.103811 · Cited by 37
Pyruvate kinase M2 in chronic inflammations: a potpourri of crucial protein–protein interactions
Patel, S., Das, A., Meshram, P., Sharma, A., Chowdhury, A., Jariyal, H., Datta, A., Sarmah, D., Nalla, L. V., Sahu, B., et al. (2021) · Cell Biology and Toxicology · doi:10.1007/s10565-021-09605-0 · Cited by 37
“In activated macrophages, the treatment with lipopolysaccharide (LPS) notably upregulates the less enzymatically active PKM2 forms (monomeric or dimeric), which result in the accumulation of succinate, an inflammatory signaling molecule which can induce the IL-1β production via stabilizing the HIF-1α by inhibiting PHD…”
BackgroundThe Role of Succinic Acid Metabolism in Ovarian Cancer
Xia, L., Zhang, H., Wang, X., Zhang, X., & Nie, K. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.769196 · Cited by 34
“Succinic acid, on the other hand, can stabilize HIFs through The PI3K signaling pathway through SUCNR1 receptor (13, 37).”
BackgroundSuccinylation and redox status in cancer cells
Dai, X., Zhou, Y., Han, F., & Li, J. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.1081712 · Cited by 37
“Mechanically, succinates accumulate within the mitochondria as a result of reversed SDH activity and inhibited respiratory chain under low oxygen stress, and these abnormally accumulated succinates are freely transported to the cytosol via the dicarboxylic acid translocator in the mitochondrial inner membrane and the…”
BackgroundZhang, D., Wang, W., Xiang, B., Li, N., Huang, S., Zhou, W., Sun, Y., Wang, X., Ma, J., Li, G., et al. (2013) · Tumor Biology · doi:10.1007/s13277-013-0781-4 · Cited by 34
“Furthermore, accumulation of succinate could also induce production of the ROS, and the latter has a role in tumorigenesis and progression.”
BackgroundInfluentialRole of Mitochondrial Mutations in Cancer
Baysal, B. E. (2006) · Endocrine Pathology · doi:10.1385/ep:17:3:203 · Cited by 39
A common pathway for genetic events leading to pheochromocytoma
Maxwell, P. H. (2005) · Cancer Cell · doi:10.1016/j.ccr.2005.07.012 · Cited by 33
Kondrashova, M. N., Zakharchenko, M. V., & Khunderyakova, N. (2009) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2009.04.020 · Cited by 33
Mito-Nuclear Communication in Hepatocellular Carcinoma Metabolic Rewiring
Mello, T., Simeone, I., & Galli, A. (2019) · Cells · doi:10.3390/cells8050417 · Cited by 34
“Succinate is the end-product formed by PHD during the α-ketoglutarate-dependent hydroxylation of HIF-1α, and as such, inhibits PHD activity [171].”
BackgroundPattern-Recognition Receptors and Immunometabolic Reprogramming: What We Know and What to Explore
Kumar, V., & Stewart, J. H. (2024) · Journal of Innate Immunity · doi:10.1159/000539278 · Cited by 39
Bardella, C., Olivero, M., Lorenzato, A., Geuna, M., Adam, J., O'Flaherty, L., Rustin, P., Tomlinson, I., Pollard, P. J., & Di Renzo, M. F. (2012) · Molecular and Cellular Biology · doi:10.1128/mcb.06160-11 · Cited by 33
“In agreement with previous reports (42, 51), we found that FH loss in normal kidney cells leads to both HIF-1 and HIF-2 accumulation but that these factors are not required for protection from apoptosis in this context.”
BackgroundResultThe Evolving Role of Succinate in Tumor Metabolism: An 18F-FDG–Based Study
Garrigue, P., Bodin-Hullin, A., Balasse, L., Fernandez-Sauze, S., Essamet, W., Dignat‐George, F., Pacák, K., Guillet, B. A., & Taïeb, D. (2017) · Journal of Nuclear Medicine · doi:10.2967/jnumed.117.192674 · Cited by 33
“Succinate has been shown to stabilize HIF-a via inhibition of prolyl hydroxylases in the cytosol, suggesting a mechanistic link between SDHx mutations, high tumor vascularity, and the 18F-FDG uptake profile in the absence of VHL mutations (12,32).”
BackgroundMolecular Pathogenesis of Gastrointestinal Stromal Tumor: A Paradigm for Personalized Medicine
Dermawan, J. K. T. K., & Rubin, B. P. (2021) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathol-042220-021510 · Cited by 34
Succinate receptor 1 inhibits mitochondrial respiration in cancer cells addicted to glutamine
Rabe, P., Liebing, A., Krumbholz, P., Kraft, R., & Stäubert, C. (2021) · Cancer Letters · doi:10.1016/j.canlet.2021.11.024 · Cited by 33
Bahiraii, S., Brenner, M., Yan, F., Weckwerth, W., & Heiß, E. H. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.935692 · Cited by 33
“Additionally, we also uncovered reduced succinate levels in M1 (LPS/Sfn) (see Figure 3), which could contribute to reduced HIF stabilization as well (53).”
BackgroundArginine metabolism regulates human erythroid differentiation through hypusination of eIF5A
González‐Menéndez, P., Phadke, I., Olive, M. E., Joly, A., Papoin, J., Yan, H., Galtier, J., Platon, J., Kang, S. W. S., McGraw, K. L., et al. (2023) · Blood · doi:10.1182/blood.2022017584 · Cited by 34
Robust metabolic adaptation underlying tumor progression
Vizán, P., Mazurek, S., & Cascante, M. (2008) · Metabolomics · doi:10.1007/s11306-007-0101-3 · Cited by 35
“…another biochemical mechanism that explains how mutation in these two enzymes contributes to tumor progression has been suggested: succinate, the substrate of SDH, might translocate out of the mitochondria and inhibit the activity of prolyl hydroxylases (PHD) in the cytosol (Selak et al., 2005).”
BackgroundDorai, T., Sawczuk, I. S., Pastorek, J., Wiernik, P. H., & Dutcher, J. P. (2006) · Cancer Investigation · doi:10.1080/07357900601062321 · Cited by 32
“Recent studies link succinate accumulation to the hypoxic proliferation signal (125).”
BackgroundSaito, Y., Ishii, K., Aita, Y., Ikeda, T., Kawakami, Y., Shimano, H., Hara, H., & Takekoshi, K. (2015) · Neurochemical Research · doi:10.1007/s11064-015-1738-3 · Cited by 35
Tena, I., Gupta, G., Tajahuerce, M., Benavent, M., Cifrián, M., Falcón, A., Fonfría, M., Olmo-García, M. I. D., Reboll, R., Conde-Moreno, A. J., et al. (2018) · Clinical Medicine Insights Oncology · doi:10.1177/1179554918763367 · Cited by 33
Metabolic control of renin secretion
Peti‐Peterdi, J., Gevorgyan, H. A., Lam, L., & Riquier‐Brison, A. (2012) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-012-1130-y · Cited by 32
“As a result, succinate/GPR91 signaling is now implicated in the pathomechanism of diabetic nephropathy [24, 28, 42, 43], retinopathy [35], obesity [31], heart ischemia [1] and hypertension [12, 34], liver disease [5], immune [33] and blood disorders [11], and possibly also connected to aging and cancer [38].”
Li, A. M., & Ye, J. (2023) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-062822-120857 · Cited by 31
Oxygen Concentration Controls Epigenetic Effects in Models of Familial Paraganglioma
Her, Y. F., Nelson-Holte, M. H., & Maher, L. J. (2015) · PLoS ONE · doi:10.1371/journal.pone.0127471 · Cited by 34
“5 mM and 20 mMDMS treatment of HEK293 cells in normoxia [9,11].”
BackgroundMethodInfluentialMetabolic modulation of cancer: a new frontier with great translational potential
Kinnaird, A. S., & Michelakis, E. D. (2015) · Journal of Molecular Medicine · doi:10.1007/s00109-014-1250-2 · Cited by 32
Silkin, Y. A., Oyedotun, K. S., & Lemire, B. D. (2006) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2006.11.017 · Cited by 32
Paragangliomas of the Carotid Body: Current Management Protocols and Review of Literature
Naik, S. M., Shenoy, A. M., Nanjundappa, Halkud, R., Chavan, P., Sidappa, K., Amirtham, U., & Gupta, S. (2013) · Indian Journal of Surgical Oncology · doi:10.1007/s13193-013-0249-4 · Cited by 32
Hematopoietic stem cell lineage specification
Pouzolles, M., Oburoglu, L., Taylor, N. N., & Zimmermann, V. S. (2016) · Current Opinion in Hematology · doi:10.1097/moh.0000000000000260 · Cited by 37
Structure‐based discovery of new selective small‐molecule sirtuin 5 inhibitors
Liu, S., Ji, S., Yu, Z., Wang, H., Cheng, X., Li, W., Li, J., Yu, Y., Chen, Q., Yang, L., et al. (2017) · Chemical Biology & Drug Design · doi:10.1111/cbdd.13077 · Cited by 34
Abboud, M. I., McAllister, T. E., Leung, I. K. H., Chowdhury, R., Jorgensen, C., Domene, C., Mecinović, J., Lippl, K., Hancock, R. L., Hopkinson, R. J., et al. (2018) · Chemical Communications · doi:10.1039/c8cc00387d · Cited by 31
The PHD1 oxygen sensor in health and disease
Kennel, K. B., Burmeister, J., Schneider, M. A., & Taylor, C. T. (2018) · The Journal of Physiology · doi:10.1113/jp275327 · Cited by 34
“Intracellular accumulation of succinate through inhibition of succinate dehydrogenase is linked to a decreased activity of the PHDs via a mechanism of product inhibition (Selak et al. 2005).”
BackgroundFaienza, F., Lambrughi, M., Rizza, S., Pecorari, C., Giglio, P., Viloria, J. S., Allega, M. F., Chiappetta, G., Vinh, J., Pacello, F., et al. (2020) · Biochemical Pharmacology · doi:10.1016/j.bcp.2020.113869 · Cited by 31
Yuan, T., Zhou, T., Qian, M., Du, J., Liu, Y., Wang, J., Li, Y., Fan, G., Yan, F., Dai, X., et al. (2022) · Hepatology · doi:10.1002/hep.32621 · Cited by 33
“Mechanistically, accumulated succinate imposes its tumor‐promoting functions through interacting with three major pathways: (1) inhibiting alpha‐ketoglutarate– dependent dioxygenase including histone and DNA demethylases, leading to hypermethylation and downregulation of key genes associated with differentiation[11,31…”
BackgroundNeurobiology of the carotid body
López‐Barneo, J. (2022) · Handbook of clinical neurology · doi:10.1016/b978-0-323-91534-2.00010-2 · Cited by 35
Ricci, L., Stanley, F. U., Eberhart, T., Mainini, F., Sumpton, D. P., & Cardaci, S. (2023) · Cell Death and Disease · doi:10.1038/s41419-023-05927-5 · Cited by 34
Feocromocitoma: actualización diagnóstica y terapéutica
Oleaga, L., & Goñi, F. (2008) · Endocrinología y Nutrición · doi:10.1016/s1575-0922(08)70669-7 · Cited by 33
Schlisio, S. (2009) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2009.00881.x · Cited by 33
“Interestingly, three major enzymes of the Krebs cycle (SDH, FH, IDH) have been recently identified as bonafide tumour suppressors, but more importantly, inactivation in either of them directly affects EglN activity [9, 10, 14, 71].”
BackgroundInfluentialVerma, A. M. (2006) · Current Opinion in Clinical Nutrition & Metabolic Care · doi:10.1097/01.mco.0000232895.28674.79 · Cited by 32
Stress responses in stromal cells and tumor homeostasis
Vitale, I., Manic, G., Galassi, C., & Galluzzi, L. (2019) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2019.04.004 · Cited by 33
Mitochondria, Apoptosis and Autoimmunity
Pinkoski, M. J., Waterhouse, N. J., & Green, D. R. (2005) · KARGER eBooks · doi:10.1159/000090772 · Cited by 33
Zoccarato, F., Cavallini, L., & Alexandre, A. (2009) · Journal of Bioenergetics and Biomembranes · doi:10.1007/s10863-009-9238-2 · Cited by 31
Hypoxia-Induced Signaling in Gut and Liver Pathobiology
Solanki, S. A., & Shah, Y. M. (2023) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathmechdis-051122-094743 · Cited by 34
Lim, E. Y., Lee, S., Shin, H. S., & Kim, G.-D. (2023) · Antioxidants · doi:10.3390/antiox12112016 · Cited by 35
Hypoxia-inducible C-to-U coding RNA editing downregulates SDHB in monocytes
Baysal, B. E., de Jong, K., Liu, B., Wang, J., Patnaik, S. K., Wallace, P. K., & Taggart, R. T. (2013) · PeerJ · doi:10.7717/peerj.152 · Cited by 31
“Succinate and reactive oxygen species that accumulate upon SDH inactivation were implicated as downstream messengers leading to stabilization of HIF1α in normoxic conditions (Selak et al., 2005; Guzy et al., 2008).”
BackgroundGlutamine, Glucose and other Fuels for Cancer
Ruiz-Pérez, M. V., Sánchez‐Jiménez, F., Alonso, F. J., Segura, J., Márquez, J., & Medina, M. Á. (2014) · Current Pharmaceutical Design · doi:10.2174/13816128113199990482 · Cited by 31
Corrado, M., Scorrano, L., & Campello, S. (2016) · Oncotarget · doi:10.18632/oncotarget.8727 · Cited by 31
“The oncometabolites succinate and fumarate, which both accumulate due to mutations inactivating SDH or FH, inhibit HIF1α degradation, so causing pseudo-hypoxia and favouring tumour progression [58],[59],[60],[61].”
BackgroundVerma, M., Kipari, T. M. J., Zhang, Z., Man, T. Y., Forster, T., Homer, N. Z. M., Seckl, J. R., Holmes, M. C., & Chapman, K. E. (2017) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2017.11.015 · Cited by 31
“It is an important sensor of ischemia: its substrate, succinate, is an inducer of inflammation (Chouchani et al., 2014; Tannahill et al., 2013) and accumulation of either succinate or its product, fumarate can cause pseudo-hypoxia (Selak et al., 2005; Isaacs et al., 2005).”
BackgroundFumarase is involved in DNA double-strand break resection through a functional interaction with Sae2
Leshets, M., Ramamurthy, D., Lisby, M., Lehming, N., & Pines, O. (2017) · Current Genetics · doi:10.1007/s00294-017-0786-4 · Cited by 33
Expression of Hypoxia-Inducible Factor 1α (HIF-1α) and Genes of Related Pathways in Altered Gravity
Vogel, J., Thiel, C. S., Tauber, S., Stockmann, C., Gassmann, M., & Ullrich, O. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20020436 · Cited by 33
“Succinate itself inhibits prolyl-hydrogenases [77] that are crucial for continuous normoxic HIF1a degradation.”
BackgroundPheochromocytomas and Paragangliomas: Bypassing Cellular Respiration
Cascón, A., Remacha, L., Calsina, B., & Robledo, M. (2019) · Cancers · doi:10.3390/cancers11050683 · Cited by 33
“Apart from the aforementioned CIMP profile, the accumulation of succinate competitively inhibits the family of prolyl hydroxylase domain-containing proteins (PHD1-3), leading to hypoxia-inducible factor 1 α (HIF-1α) stabilization under normoxic conditions, and contributing to activation of the pseudohypoxic pathway [1…”
BackgroundmicroRNAs Tune Oxidative Stress in Cancer Therapeutic Tolerance and Resistance
Zhang, W. C. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20236094 · Cited by 29
“It is not surprising that accumulated succinate due to a loss of function of succinate dehydrogenase could activate the pseudohypoxia signaling pathway by repressing PHD2 as reported previously [16].”
BackgroundMacklin, P. S., Yamamoto, A., Browning, L., Hofer, M., Adam, J., & Pugh, C. W. (2020) · The Journal of Pathology · doi:10.1002/path.5402 · Cited by 33
“In a manner analogous to FH deficiency, loss of functional SDH leads to cellular accumulation of succinate, a 2-OG analogue that can inhibit PHD function and thus stabilises HIF [94,101].”
BackgroundThe metabolic landscape of urological cancers: New therapeutic perspectives
Miranda‐Gonçalves, V., Lameirinhas, A., Henrique, R., Baltazar, F., & Jerónimo, C. (2020) · Cancer Letters · doi:10.1016/j.canlet.2020.02.034 · Cited by 33
Mitochondrial Kinases and the Role of Mitochondrial Protein Phosphorylation in Health and Disease
Kotrasová, V., Keresztesová, B., Ondrovičová, G., Bauer, J., Havalová, H., Pevala, V., Kutějová, E., & Kunová, N. (2021) · Life · doi:10.3390/life11020082 · Cited by 35
Rapid determination of tricarboxylic acid cycle enzyme activities in biological samples
Gonçalves, S., Paupe, V., Dassa, E. P., Brière, J.-J., Favier, J., Gimenez‐Roqueplo, A., Bénit, P., & Rustin, P. (2010) · BMC Biochemistry · doi:10.1186/1471-2091-11-5 · Cited by 32
“[34]”
Jiang, W., Zhu, Z., & Thompson, H. J. (2008) · Molecular Carcinogenesis · doi:10.1002/mc.20425 · Cited by 32
Kuo, C., Cheng, C.-T., Hou, P., Lin, Y.-P., Ma, H., Chung, Y., Chi, K. K., Chen, Y., Li, W., Kung, H.-J., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.8570 · Cited by 32
“Mutations in SDH or FH cause succinate or fumarate to accumulate and compete with α-ketoglutarate (α-KG) for PHD binding, thereby inhibiting PHD and stabilizing HIF-1α [31, 32].”
Hypoxia and Metastasis in Breast Cancer
Rundqvist, H., & Johnson, R. S. (2010) · Current topics in microbiology and immunology · doi:10.1007/82_2010_77 · Cited by 33
The role of mitochondrial damage-associated molecular patterns in acute pancreatitis
Zhou, Y., Huang, X., Jin, Y., Qiu, M., Ambe, P. C., Basharat, Z., & Hong, W. (2024) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2024.116690 · Cited by 32
The regulation of cell metabolism by hypoxia and hypercapnia
Reddan, B., & Cummins, E. P. (2025) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2025.108252 · Cited by 34
“Moreover, metabolic dysregulation e.g. changes in succinate and fumarate can also contribute to the stabilization of HIF-1 a (32).”
Beadling, C., Patterson, J., Justusson, E., Nelson, D., Pantaleo, M. A., Hornick, J. L., Chacon, M. R., Corless, C. L., & Heinrich, M. C. (2013) · Cancer Medicine · doi:10.1002/cam4.57 · Cited by 30
“The succinate that accumulates when SDH complex activity is impaired leads to reduced turnover of hypoxia-induced factor 1 alpha (HIF1Α) and heightened expression of HIF1A target genes including vascular endothelial growth factor [21].”
BackgroundSurvival of the fittest: metabolic adaptations in cancer
Berardi, M. J., & Fantin, V. R. (2010) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2010.10.001 · Cited by 30
Borsi, E., Perrone, G., Terragna, C., Martello, M., Zamagni, E., Tacchetti, P., Pantani, L., Brioli, A., Dico, A. F., Zannetti, B. A., et al. (2014) · Experimental Cell Research · doi:10.1016/j.yexcr.2014.09.018 · Cited by 30
“[12] M.”
BackgroundFlores, R. E., Brown, A. K., Taus, L. J., Khoury, J., Glover, F., Kami, K., Sarangarajan, R., Walshe, T. E., Narain, N. R., Kiebish, M. A., et al. (2018) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2018.03.012 · Cited by 31
The CIMP-high phenotype is associated with energy metabolism alterations in colon adenocarcinoma
Fedorova, M., Krasnov, G. S., Lukyanova, E., Zaretsky, A. R., Dmitriev, A. A., Melnikova, N. V., Moskalev, A., Kharitonov, S., Pudova, E. A., Guvatova, Z. G., et al. (2019) · BMC Medical Genetics · doi:10.1186/s12881-019-0771-5 · Cited by 31
“The HIF1-a transcription factor regulates many genes involved in carcinogenesis and tumor angiogenesis [91].”
BackgroundLiu, Y., Meng, F., Wang, J., Liu, M., Yang, G., Song, R., Zheng, T., Liang, Y., Zhang, S., Yin, D., et al. (2019) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-18-4113 · Cited by 30
“Because of the effect of an abnormal TCA cycle on tumorigenesis (35), we examined whether OGDHL could regulate pancreatic cancer growth.”
BackgroundBayley, J., Bausch, B., Rijken, J. A., van Hulsteijn, L. T., Jansen, J. C., Ascher, D. B., Pires, D. E. V., Hes, F. J., Hensen, E. F., Corssmit, E. P. M., et al. (2019) · Journal of Medical Genetics · doi:10.1136/jmedgenet-2019-106214 · Cited by 31
Tanaka, Y., Konishi, A., Obinata, H., & Tsuneoka, M. (2019) · Scientific Reports · doi:10.1038/s41598-019-55075-0 · Cited by 31
Urine as a biological modality for colorectal cancer detection
Chandrapalan, S., & Arasaradnam, R. P. (2020) · Expert Review of Molecular Diagnostics · doi:10.1080/14737159.2020.1738928 · Cited by 30
“defective TCA cycle (due to dysregulated enzymes) is also well described in the literature (discussion of these mechanisms is beyond the scope of the article) [51,52].”
BackgroundGenetics of Pheochromocytomas and Paragangliomas Determine the Therapeutical Approach
Sarkadi, B., Saskői, É., Butz, H., & Patócs, A. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23031450 · Cited by 33
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Elliott, R. L., & Head, J. F. (2012) · Journal of Cancer Therapy · doi:10.4236/jct.2012.34039 · Cited by 30
“HIF is a transcription factor induced under low oxygen conditions [58].”
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Hypoxia-inducible factor prolyl 4-hydroxylase inhibition in cardiometabolic diseases
Koivunen, P., Serpi, R., & Dimova, E. Y. (2016) · Pharmacological Research · doi:10.1016/j.phrs.2016.11.003 · Cited by 33
Noncoding RNAs in the Vascular System Response to Oxidative Stress
Fuschi, P., Maimone, B., Gaetano, C., & Martelli, F. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7229 · Cited by 31
“Likewise, SDHD inhibition results in succinate accumulation and succinate can also inhibit PHD/EGLN activity, preventing Hif1‐α degradation (131).”
Models of parent-of-origin tumorigenesis in hereditary paraganglioma
Hoekstra, A. S., Devilee, P., & Bayley, J. (2015) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2015.05.011 · Cited by 30
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Hypoxia-driven metabolic reprogramming of adipocytes fuels cancer cell proliferation
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“Especially, lipid uptake for the biosynthesis of cancer cell membranes will facilitate cell integrity and growth, while generation of other lipidderived biomolecules (such as steroid hormones, phospholipids, diacyglycerols etc) will further sustain cancer cell function (43).”
BackgroundD’Alessandro, A., Nouraie, M. S., Zhang, Y., Cendali, F. I., Gamboni, F., Reisz, J. A., Zhang, X., Bartsch, K. W., Galbraith, M. D., Espinosa, J. M., et al. (2023) · Haematologica · doi:10.3324/haematol.2023.283288 · Cited by 31
“This observation is relevant in light of the role of these carboxylic acids, especially succinate, in the stabilization of hypoxia inducible factor 1 alpha,(43) and activation of its transcriptional targets, including interleukin 1beta.”
BackgroundRole of HIF in fish inflammation
Shi, X., Gao, F., Zhao, X., Pei, C., Zhu, L., Zhang, J., Li, C., Li, L., & Kong, X. (2023) · Fish & Shellfish Immunology · doi:10.1016/j.fsi.2023.109222 · Cited by 28
Succinate as a signaling molecule in the mediation of liver diseases
Chen, H., Jin, C., Xie, L. H., & Wu, J. H. (2023) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2023.166935 · Cited by 34
The Role of PKM2 in Multiple Signaling Pathways Related to Neurological Diseases
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Endothelial FUNDC1 Deficiency Drives Pulmonary Hypertension
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“30 In addition, glycolysis products (ie, pyruvate) can increase HIF protein levels in EC.”
Gut commensals-derived succinate impels colonic inflammation in ulcerative colitis
Dalal, R., Sadhu, S., Batra, A., Goswami, S., Dandotiya, J., Vinayakadas, K., V, Yadav, R., Singh, V., Chaturvedi, K., Kannan, R., et al. (2025) · npj Biofilms and Microbiomes · doi:10.1038/s41522-025-00672-3 · Cited by 37
“Additionally,theaccumulationofintracellular succinate in the cytosol inhibitsprolyl hydroxylase (PHD) enzymes,which allows the stabilization of HIF-1 α -mediated Th9 cells 17,18 .”
Flynn, A., Pattison, A., Balachander, S., Boehm, E., Bowen, B., Dwight, T., Rossello, F. J., Hofmann, O., Martelotto, L. G., Zethoven, M., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-57595-y · Cited by 37
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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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