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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
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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Sorted by citations
Items 1,301–1,400 of 2,106
Hypoxia Stabilizes Type 2 Deiodinase Activity in Rat Astrocytes
Lamirand, A., MERCIER, G., Ramaugé, M., Pierre, M., & Courtin, F. (2007) · Endocrinology · doi:10.1210/en.2007-0625 · Cited by 19
“inhibition (38), also increases D2 activity, suggesting a link”
BackgroundIs oxygen a key factor in the lipodystrophy phenotype?
Gentil, C., Jan, S. L., Philippe, J., Leibowitch, J., Sonigo, P., Germain, S., & Piétri‐Rouxel, F. (2006) · Lipids in Health and Disease · doi:10.1186/1476-511x-5-27 · Cited by 19
Mailloux, R. J. (2023) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2023.119639 · Cited by 20
Deep and dynamic metabolic and structural imaging in living tissues
Liu, K., Cao, H., Shashaty, K., Yu, L.-Y., Spitz, S., Pramotton, F. M., Wan, Z., Kan, E. L., Tevonian, E. N., Levy, M. S., et al. (2024) · Science Advances · doi:10.1126/sciadv.adp2438 · Cited by 21
From Transcriptional Profiling to Tumor Biology in Pheochromocytoma and Paraganglioma
Cascón, A., & Tennant, D. A. (2012) · Endocrine Pathology · doi:10.1007/s12022-012-9195-x · Cited by 17
Sakai, C., Tomitsuka, E., Miyagishi, M., Harada, S., & Kita, K. (2013) · Mitochondrion · doi:10.1016/j.mito.2013.08.009 · Cited by 19
Jaeger, C., Tellström, V., Zurek, G., König, S., Eimer, S., & Kammerer, B. (2014) · Metabolomics · doi:10.1007/s11306-014-0637-y · Cited by 18
“Mutations in SDH in humans have been implicated in oncogenesis (Selak et al. 2005).”
Backgroundγ-Glutamylcyclotransferase, a novel regulator of HIF-1α expression, triggers aerobic glycolysis
Taniguchi, K., Kageyama, S., Moyama, C., Ando, S., Ii, H., Ashihara, E., Horinaka, M., Sakai, T., Kubota, S., Kawauchi, A., et al. (2021) · Cancer Gene Therapy · doi:10.1038/s41417-020-00287-0 · Cited by 18
Metabolic Rewiring in Radiation Oncology Toward Improving the Therapeutic Ratio
van Gisbergen, M. W., Zwilling, E., & Dubois, L. J. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.653621 · Cited by 20
Sanchez, M., Hamel, D., Bajon, E., Duhamel, F., Bhosle, V. K., Zhu, T., Rivera, J. C., Dabouz, R., Nadeau‐Vallée, M., Sitaras, N., et al. (2022) · Cells · doi:10.3390/cells11142185 · Cited by 18
“Although this role is essential to life, succinate and its precursor succinyl-CoA are also byproducts of several other cellular reactions such as HIF1a stabilization and DNA methylation [3,4].”
BackgroundRicketts, C. J., Killian, J. K., Vocke, C. D., Wang, Y., Merino, M. J., Meltzer, P. S., & Linehan, W. M. (2022) · PLoS ONE · doi:10.1371/journal.pone.0278108 · Cited by 18
“In a similar manner to HLRCC tumors, the loss of succinate dehydrogenase activity results in suppression of oxidative phosphorylation and increased intracellular succinate can inhibit the prolyl hydroxylases [14, 19].”
BackgroundSych, K., Nold, S. P., Pfeilschifter, J. M., Vutukuri, R., Meisterknecht, J., Wittig, I., Frank, S., & Goren, I. (2023) · Journal of Molecular Medicine · doi:10.1007/s00109-022-02280-6 · Cited by 19
“Metabolites were proven to regulate oncogenic activity [5], as well as other pathophysiological processes like inflammation [6, 7] and immune response [8].”
BackgroundThe Interplay between Dysregulated Metabolism and Epigenetics in Cancer
Bassal, M. A. (2023) · Biomolecules · doi:10.3390/biom13060944 · Cited by 19
Wang, Y., Liu, B., Li, F., Zhang, Y., Gao, X., Wang, Y., & Zhou, H. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1274239 · Cited by 18
“Notably, succinate serves not only as a substrate for mitochondrial SDHx but also as a product of cytoplasmic PHDs (33, 69, 71 – 74).”
BackgroundFu, Z., Deng, M., Zhou, Q., Li, S., Liu, W., Cao, S. “., Zhang, L., Deng, Y. H., & Xi, S. (2024) · The Science of The Total Environment · doi:10.1016/j.scitotenv.2024.174538 · Cited by 20
Ogura, M., Yamaki, J., Homma, M. K., & Homma, Y. (2014) · FEBS Letters · doi:10.1016/j.febslet.2014.06.044 · Cited by 18
“A previous study had provided evidence that knockdown of the SDHD subunit does not lead to increased ROS production despite a significant reduction in the amount of expressed SDHD protein in HEK293 cells [28].”
BackgroundMultiple painful cutaneous nodules and renal mass
Rothman, A., Glenn, G. M., Choyke, L. T., Srinivasan, R., Linehan, W. M., & Cowen, E. W. (2006) · Journal of the American Academy of Dermatology · doi:10.1016/j.jaad.2006.06.026 · Cited by 18
Bakalov, V., Amathieu, R., Triba, M. N., et al. (2016) · Metabolites · doi:10.3390/metabo6040047 · Cited by 18
“Succinate is a TCA cycle metabolite and plays an important role in the production of ATP; in addition, succinate contributes to the stabilization of transcription factor hypoxia-inducible factor-1α (HIF-1α) with subsequent transcription of proinflammatory cytokines [28,29].”
Backgroundα‐Tocopheryl Phosphate Induces VEGF Expression via CD36/PI3Kγ in THP‐1 Monocytes
Zingg, J.-M. A., Azzi, A., & Meydani, M. (2017) · Journal of Cellular Biochemistry · doi:10.1002/jcb.25871 · Cited by 20
Metabolic Alterations at the Crossroad of Aging and Oncogenesis
Raffaghello, L., & Longo, V. D. (2017) · International review of cytology · doi:10.1016/bs.ircmb.2017.01.003 · Cited by 19
“In addition, accumulation of fumarate and succinate participates in oncogenic signaling through: (i) modification of cysteine residues in proteins which confers a state of constitutive activation of the antioxidant defense pathway mediated by NF-E2-related factor (NRF2), that generates a reductive milieu and promotes…”
BackgroundKim, K. H., Lee, H. H., Yoon, Y. E., Na, J. C., Kim, S. Y., Cho, Y. I., Hong, S. J., & Han, W. K. (2017) · Oncotarget · doi:10.18632/oncotarget.23087 · Cited by 17
“Although activation of HIF and VEGF have been described mostly in clear cell RCC, HIF activity in other subtypes of RCC has been suggested [20].”
BackgroundThymosin β4 promotes autophagy and repair via HIF-1α stabilization in chronic granulomatous disease
Renga, G., Oikonomou, V., Moretti, S., Stincardini, C., Bellet, M. M., Pariano, M., Bartoli, A., Brancorsini, S., Mosci, P., Finocchi, A., et al. (2019) · Life Science Alliance · doi:10.26508/lsa.201900432 · Cited by 17
“Prolyl hydroxylases can be inhibited through succinate upon accumulation by inhibition of succinate dehydrogenase (Selak et al, 2005).”
BackgroundHoang, M., & Joseph, J. W. (2020) · Islets · doi:10.1080/19382014.2020.1802183 · Cited by 17
“It has been shown that succinate and fumarate can regulate PHD activity and HIF stabilization.(100,101) A role for succinate has been shown by inhibiting succinate dehydrogenase, which elevated cytosolic succinate levels, and led to a reduction in PHD activity.”
BackgroundKhazal, F. A., Kang, S., Holte, M. N., et al. (2020) · The FASEB Journal · doi:10.1096/fj.202002100r · Cited by 18
Zhao, Z., Rothery, R. A., & Weiner, J. H. (2006) · Biochemistry and Cell Biology · doi:10.1139/o06-188 · Cited by 18
“As mentioned earlier, metabolic imbalance and dysfunction of the tricarboxylic acid cycle can also trigger tumor formation (Briere et al. 2005, 2006; Dahia et al. 2005; Pollard et al. 2005; Selak et al. 2005; Vanharanta et al. 2006).”
BackgroundInfluentialKonieczna, A., Szczepańska, A., Sawiuk, K., Łyżeń, R., & Węgrzyn, G. (2014) · Medical Hypotheses · doi:10.1016/j.mehy.2014.11.016 · Cited by 17
Chen, C.-L., Ishihara, T., Pal, S., Huang, W., Ogasawara, E., Chang, C., & Ishihara, N. (2024) · Mitochondrion · doi:10.1016/j.mito.2024.101952 · Cited by 17
Serum lipoprotein–derived fatty acids regulate hypoxia-inducible factor
Shao, W., Hwang, J., Liu, C., Mukhopadhyay, D., Zhao, S., Shen, M., Alpergin, E. S. S., Wolfgang, M. J., Farber, S. A., & Espenshade, P. J. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra120.015238 · Cited by 17
“Accumulation of the TCA cycle intermediates succinate and fumarate can inhibit PHD activity in cells (29, 30), but these metabolites were unchanged or decreased upon lipoprotein depletion (Fig.”
BackgroundLipid Metabolism in Cancer Cells
Zheng, M., Wang, W., Liu, J., Zhang, X., & Zhang, R. (2021) · Advances in experimental medicine and biology · doi:10.1007/978-981-33-6785-2_4 · Cited by 19
Hypoxia signaling and oxygen metabolism in cardio-oncology
Baik, A. H. (2022) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2021.12.013 · Cited by 20
Martinelli, S., Riverso, M., Mello, T., Amore, F., Parri, M., Simeone, I., Mannelli, M., Maggi, M., & Rapizzi, E. (2022) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2022.111594 · Cited by 17
“Indeed, tumours mutated for SDHC or SDHD are usually benign, whereas those mutated for SDHB are very often malignant (Timmers et al., 2007).”
BackgroundGermanova, E. L., Khmil, N. V., Pavlik, L. L., Mikheeva, I. B., Mironova, G. D., & Lukyanova, L. D. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232214248 · Cited by 17
Owusu-Ansah, M., Guptan, N., Alindogan, D., Morizono, M., & Caldovic, L. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24076754 · Cited by 18
You, Y., Park, S., Kwon, E., Kim, Y.-A., Hur, Y. M., Lee, G. I., Kim, S. M., Song, J. M., Kim, Y. J., Kim, Y. H., et al. (2024) · Environmental Science and Pollution Research · doi:10.1007/s11356-023-31774-0 · Cited by 19
“The pathogenesis of mutations and deficiencies in the CII subunit appears to be related to succinate accumulation, which is associated with a con-trol mechanism that activates the hypoxic program of cells (Selak et al. 2005).”
BackgroundRewiring of RNA methylation by the oncometabolite fumarate in renal cell carcinoma
Fitzsimmons, C. M., Mandler, M. D., Lunger, J. C., Chan, D., Maligireddy, S. S., Schmiechen, A. C., Gamage, S. T., Link, C. N., Jenkins, L. M. M., Chan, K. C., et al. (2024) · NAR Cancer · doi:10.1093/narcan/zcae004 · Cited by 18
Zhang, X., Zhang, W., Zhao, L., et al. (2024) · Animals · doi:10.3390/ani14040561 · Cited by 17
“A reduction in Cd-induced cellular damage was achieved by increasing the activities of ACP and AKP, as well as promoting the metabolism of phosphate in the organism.”
BackgroundChang, Y.-L., Hsieh, M., Chang, W., Wang, H., Lin, M., Wang, C., Lou, P., & Teng, S. (2014) · Antioxidants and Redox Signaling · doi:10.1089/ars.2014.5966 · Cited by 17
Hyperpolarized [1,4‐13C]‐diethylsuccinate: a potential DNP substrate for in vivo metabolic imaging
Billingsley, K. L., Josan, S., Park, J. M., Tee, S. S., Spielman-Sun, E., Hurd, R. E., Mayer, D., & Spielman, D. M. (2014) · NMR in Biomedicine · doi:10.1002/nbm.3071 · Cited by 17
Functional Consequences of Succinate Dehydrogenase Mutations
Opocher, G., & Schiavi, F. (2011) · Endocrine Practice · doi:10.4158/ep11070.ra · Cited by 17
Merlo, A., Bernardo‐Castiñeira, C., Sáenz‐de‐Santa‐María, I., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.14265 · Cited by 17
“By contrast, the mitochondrial SDH complex activity, related with tumorigenesis and supposedly involved in HIF-1α regulation [5], does not appear to have a direct effect on HIF-1α-dependent miR-210 overexpression but it favors it via a mechanism which has not been clearly defined as yet.”
BackgroundNon-canonical roles for metabolic enzymes and intermediates in malignant progression and metastasis
Williams, D., & Fingleton, B. (2019) · Clinical & Experimental Metastasis · doi:10.1007/s10585-019-09967-0 · Cited by 16
Pranzini, E., Leo, A., Rapizzi, E., Ramazzotti, M., Magherini, F., Giovannelli, L., Caselli, A., Cirri, P., Taddei, M. L., & Paoli, P. (2019) · Molecular Carcinogenesis · doi:10.1002/mc.23107 · Cited by 17
Facchin, C., Pérez-Liva, M., Garofalakis, A., Viel, T., Certain, A., Balvay, D., Yoganathan, T., Woszczyk, J., Sousa, K. D., Sourdon, J., et al. (2020) · Theranostics · doi:10.7150/thno.40687 · Cited by 19
“In these patients, loss of succinate dehydrogenase (SDH) function has been associated with succinate accumulation [40], leading to a pseudohypoxic phenotype [41] and therefore to increased anaerobic glycolysis and angiogenesis [42-45].”
BackgroundSaxena, N., Beraldi, E., Fazli, L., Somasekharan, S. P., Adomat, H. H., Zhang, F., Molokwu, C. N., Gleave, A., Nappi, L., Nguyen, K., et al. (2021) · EMBO Molecular Medicine · doi:10.15252/emmm.202013427 · Cited by 16
“Increased succinate inhibits activity of the succinate precursor 2-oxoglutarate (2-OG)-dependent enzymes resulting in stabilization of HIF1a (Selak et al, 2005), increased DNA methylation (Yang & Pollard, 2013), and also post-translational modification of various proteins via succinylation (Zhang…”
BackgroundInfluentialThe non-canonical functions of HIF prolyl hydroxylases and their dual roles in cancer
Yu, M., Lun, J., Zhang, H., Zhu, L., Zhang, G., & Fang, J. S. (2021) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2021.105982 · Cited by 20
Silas, Y., Singer, E., Das, K., Lehming, N., & Pines, O. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2026595118 · Cited by 18
Control of topoisomerase II activity and chemotherapeutic inhibition by TCA cycle metabolites
Lee, J. H., Mosher, E. P., Lee, Y., Bumpus, N. N., & Berger, J. M. (2021) · Cell chemical biology · doi:10.1016/j.chembiol.2021.08.014 · Cited by 18
Liu, W., Pan, P.-Y., Sun, Y., Wang, J., Zhou, H., Xie, X., Duan, Z., Dong, H.-Y., Chen, W., Zhang, L.-D., et al. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2021.794735 · Cited by 19
“Three iron-sulfur (Fe-S) clusters in SDHB facilitate the transfer of electrons from FADH2 to ubiquinone, which is bound via the membrane-embedded SDHC and SDHD subunits (25, 26).”
BackgroundNovel Genes Associated with the Development of Carotid Paragangliomas
Snezhkina, A. V., Lukyanova, E., Fedorova, M., Kalinin, D. V., Melnikova, N. V., Stepanov, O. A., Kiseleva, M. V., Каприн, А. Д., Pudova, E. A., & Kudryavtseva, A. V. (2019) · Molecular Biology · doi:10.1134/s0026893319040137 · Cited by 17
Phosphofructokinase Platelet Overexpression Accelerated Colorectal Cancer Cell Growth and Motility
Lu, T., Yang, Y.-F., Cheng, C., et al. (2023) · Journal of Cancer · doi:10.7150/jca.82738 · Cited by 17
“Several mechanisms have been suggested to modulate the Warburg effect, including mitochondrial defects, a hypoxic environment, oncogenic signal activation, and metabolic enzyme deregulation [7-13].”
BackgroundIshii, T., Yasuda, K., Miyazawa, M., Mitsushita, J., Johnson, T. E., Hartman, P. S., & Ishii, N. (2016) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2016.02.013 · Cited by 16
“In tumor tissues, the inactivation of SDH activity and succinate accumulation inhibited prolyl-hydroxylation of hypoxia inducible factors (HIF) 1alpha and 2alpha, which is an essential step for its degradation through the complex VHL-ElonginD-C-Cul2 (Selak et al., 2005).”
BackgroundThe role of hypoxia inducible factor-1 in cell metabolism – a possible target in cancer therapy
Aiba, R. S. B., Dimova, E. Y., Görlach, A., & Kietzmann, T. (2006) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.10.4.583 · Cited by 17
“This enhanced HIF-1α stability might be one of the reasons for the inherited cancer syndromes observed in clinical cases characterised with SDH and FH mutations [115-120].”
BackgroundA Phenotypic Perspective on Mammalian Oxygen Sensor Candidates
Baysal, B. E. (2006) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1353.024 · Cited by 17
Nengroo, M. A., Klein, A. T., Carr, H. S., Vidal-Cruchez, O., Sahu, U., McGrail, D. J., Sahni, N., Thompson, N. B., Faull, P. A., Gao, P., et al. (2025) · Molecular Cell · doi:10.1016/j.molcel.2025.10.002 · Cited by 20
Li, Z., Zhen, S., Su, K., Tumber, A., Yu, Q., Dong, Y., McDonough, M. A., Schofield, C. J., & Zhang, X. (2020) · Chemical Communications · doi:10.1039/d0cc06353c · Cited by 19
Non-canonical function of an Hif-1α splice variant contributes to the sustained flight of locusts
Ding, D., Zhang, J., Du, B., Wang, X., Hou, L., Guo, S., Chen, B., & Kang, L. (2022) · eLife · doi:10.7554/elife.74554 · Cited by 16
“This pathway controls hundreds of downstream gene expressions and is an important therapeutic target for many hypoxia- associated diseases in human (Kim and Kaelin, 2004; Masoud and Li, 2015; Selak et al., 2005).”
BackgroundRole of succinate in airway epithelial cell regulation following traumatic lung injury
Suresh, M. V., Aktay, S., Yalamanchili, G., Solanki, S. A., Sathyarajan, D. T., Arnipalli, M. S., Pennathur, S., & Raghavendran, K. (2023) · JCI Insight · doi:10.1172/jci.insight.166860 · Cited by 17
Mutations of the Electron Transport Chain Affect Lifespan and ROS Levels in C. elegans
Ősz, F., Nazir, A., Takács‐Vellai, K., & Farkas, Z. (2025) · Antioxidants · doi:10.3390/antiox14010076 · Cited by 17
“…that excess succinate levels are also characteristic of PHEO/PGL tumors, where SDH mutations cause mitochondrial succinate accumulation in the cytoplasm and HIF-1 α (hypoxia-inducible factor alpha) activation, which favors pseudohypoxia-driven tumorigenesis [160] and can lead to inflammation [161].”
Metabolic pathways in cancers: key targets and implications in cancer therapy
Vijayakumar, S. N., Sethuraman, S., & Krishnan, U. M. (2015) · RSC Advances · doi:10.1039/c5ra06505d · Cited by 16
Pérez, F. G., Gil, A. L., Robledo, M., et al. (2016) · Endocrinología y Nutrición · doi:10.1016/j.endonu.2016.07.007 · Cited by 16
Towards the routine use of in silico screenings for drug discovery using metabolic modelling
Bintener, T., Pacheco, M. P., & Sauter, T. (2020) · Biochemical Society Transactions · doi:10.1042/bst20190867 · Cited by 17
Precision Medicine in Phaeochromocytoma and Paraganglioma
Winzeler, B. F., Challis, B., & Casey, R. T. (2021) · Journal of Personalized Medicine · doi:10.3390/jpm11111239 · Cited by 17
“The first cluster is characterised by a pseudohypoxic signature and accelerated angiogenesis promoted by abnormal stabilization of hypoxia-inducible factor (HIF) alpha transcription [26].”
BackgroundComparing the Secretomes of Chemorefractory and Chemoresistant Ovarian Cancer Cell Populations
Lee, A. H., Peña, C. M., & Dawson, M. (2022) · Cancers · doi:10.3390/cancers14061418 · Cited by 17
Mouse Models of Human Familial Paraganglioma
Maher, L. J., III, Emily, H., Emily, M., Nicole, A., Paul, J., Nelson-Holte, M. H., Piruat, J. I., García‐Flores, P., López‐Barneo, J., & van, J. (2011) · InTech eBooks · doi:10.5772/25346 · Cited by 20
“According to the succinate (Su) accumulation hypothesis (Lee et al., 2005; Maxwell, 2005; Selak et al., 2005; Smith et al., 2007; Favier & Gimenez-Roqueplo, 2010), the disruption of SdhB yields a catalytically inactive SdhA subunit and Su accumulates in the cell due to loss of SDH activity.”
MethodNovel Hereditary Forms of Pheochromocytomas and Paragangliomas
Dahia, P. L. M. (2013) · Frontiers of hormone research · doi:10.1159/000345671 · Cited by 16
Metabolic evaluations of cancer metabolism by NMR ‐based stable isotope tracer methodologies
Tavares, L. C., Jarak, I., Nogueira, F. N., Oliveira, P. J., & Carvalho, R. A. (2014) · European Journal of Clinical Investigation · doi:10.1111/eci.12358 · Cited by 16
Huang, K. T., Dobrovic, A., & Fox, S. B. (2009) · BMC Research Notes · doi:10.1186/1756-0500-2-194 · Cited by 16
“Increased levels of fumarate and succinate inhibit PHD activity via product inhibition as well as by direct inhibition by competing with α-ketoglutarate at the PHD α-ketoglutarate binding site [6-8].”
BackgroundMitochondrial complex II regulates a distinct oxygen sensing mechanism in monocytes
Sharma, S., Wang, J., Gomez, E. C., Taggart, R. T., & Baysal, B. E. (2017) · Human Molecular Genetics · doi:10.1093/hmg/ddx041 · Cited by 16
Metabolic orchestration of T lineage differentiation and function
Yong, C. S. M., Moussa, D. A., Cretenet, G., Kinet, S., Dardalhon, V., & Taylor, N. N. (2017) · FEBS Letters · doi:10.1002/1873-3468.12849 · Cited by 16
Heesterman, B. L., de Pont, L. M. H., van der Mey, A. G. L., Bayley, J., Corssmit, E. P. M., Hes, F. J., Verbist, B. M., van Benthem, P. P. G., & Jansen, J. C. (2018) · European Journal of Human Genetics · doi:10.1038/s41431-018-0116-4 · Cited by 16
Mukaneza, Y., Cohen, A., Rivard, M.-È., Tardif, J., Deschênes, S., Ruiz, M., Laprise, C., Rosiers, C. D., & Coderre, L. (2019) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00160.2017 · Cited by 16
Catherino, W. H., Mayers, C. M., Mantzouris, T., Armstrong, A. Y., Linehan, W. M., & Segars, J. H. (2007) · Fertility and Sterility · doi:10.1016/j.fertnstert.2006.11.198 · Cited by 16
Thyroid Hormone Inactivation in Gastrointestinal Stromal Tumors
(2014) · New England Journal of Medicine · doi:10.1056/nejmc1405198 · Cited by 24
Hypoxia-inducible factor-driven glycolytic adaptations in host-microbe interactions
DeMichele, E., Buret, A. G., & Taylor, C. T. (2024) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-024-02953-w · Cited by 16
“Increased HIF-1α-driven glycolytic activity in macrophages leads to increased production of succinate, a TCA cycle intermediate which positively regulates glycolysis via inhibition of PHD activity upon accumulation in the cytosol [60, 83].”
BackgroundMacrophage Metabolic Reprogramming in Inflammatory Bowel Diseases: From Pathogenesis to Therapy
Zhang, Y.-F., Shi, T. T., Lin, Y., Zhu, Y., Lin, S., & Fang, T. (2025) · Journal of Inflammation Research · doi:10.2147/jir.s534447 · Cited by 19
Nutritional and metabolic signalling through GPCRs
Pardella, E., Ippolito, L., Giannoni, E., & Chiarugi, P. (2022) · FEBS Letters · doi:10.1002/1873-3468.14441 · Cited by 18
Foresto‐Neto, O., da Silva, A. R. P. A., Cipelli, M., Santana, F. P. R., & Câmara, N. O. S. (2023) · Kidney Research and Clinical Practice · doi:10.23876/j.krcp.23.012 · Cited by 15
“Increasing succinate in macrophages leads to inhibition of PHDs through generation of ROS by mitochondrial reverse electron transport from complex I or even by competition for the binding site of its cosubstrate, alpha-ketoglutarate [89,90].”
BackgroundGarimella, S. V., Gampa, S. C., & Chaturvedi, P. (2023) · Stem Cells and Cloning Advances and Applications · doi:10.2147/sccaa.s417842 · Cited by 16
Hou, Y., He, Y., Wang, J., Zhou, Y., Ma, B., Li, X., Shi, L., & Zhang, Q. (2023) · Clinica Chimica Acta · doi:10.1016/j.cca.2023.117530 · Cited by 15
Kazenwadel, J., Berezhnoy, G., Cannet, C., Schäfer, H., Geisler, T., Rohlfing, A., Gawaz, M., Merle, U., & Trautwein, C. (2023) · Communications Medicine · doi:10.1038/s43856-023-00365-y · Cited by 15
“This is possibly an expression of a hypoxic metabolic state, since succinic acid is able to stabilize hypoxia-inducible factor-1 α (HIF-1 α ) 57 and also to force the interleukin production 58 .”
The deep end of the metabolite pool: influences on epigenetic regulatory mechanisms in cancer
Nordgren, K. K. S., & Skildum, A. J. (2014) · European Journal of Clinical Investigation · doi:10.1111/eci.12361 · Cited by 15
Increased chemoresistance induced by inhibition of HIF‐prolyl‐hydroxylase domain enzymes
Brökers, N., Le-Huu, S. K.-A., Vogel, S., Hagos, Y., Katschinski, D. M., & Kleinschmidt, M. (2009) · Cancer Science · doi:10.1111/j.1349-7006.2009.01367.x · Cited by 16
Molecular basis for the treatment of renal cell carcinoma
Suárez, C., Morales‐Barrera, R., Muñoz‐Couselo, E., Rodon, J. A., Valverde, C. M., & Carles, J. (2010) · Clinical & Translational Oncology · doi:10.1007/s12094-010-0461-4 · Cited by 15
Bex, A., Larkin, J., & Blank, C. U. (2011) · Current Oncology Reports · doi:10.1007/s11912-011-0159-y · Cited by 15
Novel ways to target brain tumour metabolism
Stieber, D., Rahim, S. A. A., & Niclou, S. P. (2011) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.2011.588211 · Cited by 17
“In hereditary head and neck paragangliomas for instance, mutations in the gene coding for succinate dehydrogenase, involved in the mitochondrial respiratory chain complex II, leads to an accumulation of succinate, which stabilizes steady state levels of HIF1a by inhibiting HIF prolyl hydroxylases [55,56].”
BackgroundKornaczewski, E. R., Pointon, O., & Burgess, J. R. (2016) · Clinical Endocrinology · doi:10.1111/cen.13020 · Cited by 15
Новые гены, ассоциированные с образованием каротидных параганглиом
Snezhkina, A. V., Лукьянова, Е. Н., Fedorova, M., Kalinin, D. V., Melnikova, N. V., Stepanov, O. A., Kiseleva, M. V., Каприн, А. Д., Pudova, E. A., & Кудрявцева, А. В. (2019) · Molecular Biology · doi:10.1134/s0026898419040141 · Cited by 15
Hereditary Pituitary Tumor Syndromes: Genetic and Clinical Aspects
García-Guzmán, B., Portocarrero-Ortiz, L. A., Dorantes-Argandar, A., & Mercado, M. (2020) · Revista de investigaci�n Cl�nica · doi:10.24875/ric.19003186 · Cited by 15
An update on adult forms of hereditary pheochromocytomas and paragangliomas
Dariane, C., Goncalves, J., Timsit, M., & Favier, J. (2020) · Current Opinion in Oncology · doi:10.1097/cco.0000000000000694 · Cited by 14
“Abnormal stabilization of hypoxia-inducible factors (HIFa) is explained by the lack of ubiquitination in PPGL with VHL loss-of-function, or, in SDHx or FHmutated cases, by the accumulation of oncometabolites, such as succinate or fumarate, which act as competitive inhibitors of 2-OG dependent dioxygenases such as the…”
BackgroundHypothesis: Why Different Types of SDH Gene Variants Cause Divergent Tumor Phenotypes
Bayley, J., & Devilee, P. (2022) · Genes · doi:10.3390/genes13061025 · Cited by 18
Mitochondrial substrates in cancer: Drivers or passengers?
Kruspig, B., Zhivotovsky, B., & Gogvadze, V. G. (2014) · Mitochondrion · doi:10.1016/j.mito.2014.08.007 · Cited by 15
Wang, L., Cui, S., Ma, L., Kong, L., & Geng, X. (2015) · Insect Molecular Biology · doi:10.1111/imb.12189 · Cited by 14
“Excessive cytosolic succinate suppresses PHD hydroxylase activity and stabilizes HIF-1a (Selak et al., 2005).”
BackgroundRole of proton pumps in tumorigenesis
Kobliakov, V. A. (2017) · Biochemistry (Moscow) · doi:10.1134/s0006297917040010 · Cited by 15
“Inactivation of succinate dehydrogenase or fumarate hydratase induces tumor formation because of PHD inhi bition by accumulated fumarate or succinate [14, 15].”
BackgroundJanowska, J. I., Piel, S., Saliba, N., Kim, C. D., Jang, D. H., Karlsson, M., Kilbaugh, T. J., & Ehinger, J. K. (2020) · Toxicology in Vitro · doi:10.1016/j.tiv.2020.104794 · Cited by 15
“Other potential effects of succinate administration, such as oxidative stress or modification of oxygen sensing pathways (succinate accumulation may stabilize HIF-1α) (Selak et al., 2005), also need to be addressed.”
BackgroundBalnis, J., Lee, C. G., Elias, J. A., & Jaitovich, A. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.600290 · Cited by 15
“This process, which can occur even in the normoxic environment (Selak et al., 2005), could interact with wasting signals by activating hypoxia-response elements (HREs) in the genome.”
BackgroundCoenzyme Q Depletion Reshapes MCF-7 Cells Metabolism
Wang, W., Liparulo, I., Rizzardi, N., Bolignano, P., Calonghi, N., Bergamini, C., & Fato, R. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms22010198 · Cited by 17
“Interestingly, HIF-1a is directly affected by the activity of the respiratory complex II, since the succinate inhibits the prolyl-hydroxylase domain enzymes (PHDs) activity, leading to HIF-1α stabilization under normoxic conditions [40,41].”
BackgroundHensen, E. F., Goeman, J. J., Oosting, J., van der Meij, A. G. L., Hogendoorn, P. C. W., Cremers, C. W. R. J., Devilee, P., & Cornelisse, C. J. (2009) · BMC Medical Genomics · doi:10.1186/1755-8794-2-25 · Cited by 15
Dekker, P. B. D., Kuipers‐Dijkshoorn, N. J., Baelde, H. J., van der Mey, A. G. L., Hogendoorn, P. C. W., & Cornelisse, C. J. (2006) · Human Pathology · doi:10.1016/j.humpath.2006.06.013 · Cited by 15
“Other studies on hypoxia-activated pathways have reported the stabilization of hypoxia-inducible factor–1a under normoxia and subsequent expression of vascular endothelial growth factor in pheochromocytomas and paragangliomas [5,31].”
BackgroundThe mitochondrial Na+/Ca2+ exchanger NCLX is implied in the activation of hypoxia-inducible factors
Choya-Foces, C., Navarro, E., Ríos, C. D. L., López, M. G., Egea, J., Hernansanz‐Agustín, P., & Martínez-Ruiz, A. (2024) · Redox Biology · doi:10.1016/j.redox.2024.103364 · Cited by 16
“The latter is constitutively expressed, while the former is continuously synthetized and degraded and is only stable under conditions of low oxygen, high levels of hydrogen peroxide (H 2 O 2 ) or other metabolic challenges [4 – 8].”
Assessment of Mitochondrial Cell Metabolism by Respiratory Chain Electron Flow Assays
Radogna, F., Gérard, D., Dicato, M. A., & Diederich, M. F. (2021) · Methods in molecular biology · doi:10.1007/978-1-0716-1266-8_9 · Cited by 14
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
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