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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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Introduction to Structural Studies on 2-Oxoglutarate-Dependent Oxygenases and Related Enzymes
Aik, W. S., Chowdhury, R., Clifton, I. J., Hopkinson, R. J., Leissing, T. M., McDonough, M. A., Nowak, R. P., Schofield, C. J., & Walport, L. J. (2015) · Royal Society of Chemistry eBooks · doi:10.1039/9781782621959-00059 · Cited by 52
Bharadwaj, S., Singh, M. V., Kirtipal, N., & Kang, S. G. (2021) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2020.627842 · Cited by 50
Tumor Cells and Cancer-Associated Fibroblasts: An Updated Metabolic Perspective
Gentric, G., & Mechta‐Grigoriou, F. (2021) · Cancers · doi:10.3390/cancers13030399 · Cited by 52
“Mechanistically, high O-GlcNAcylation level stabilizes HIF-1α protein by diminishing α-KG levels [80], thereby promoting expression of GLUT1 [106].”
BackgroundPhysical Exercise and Epigenetic Modulation: Elucidating Intricate Mechanisms
Sanchis-Gomar, H. P.-G., & a-Gimenez, J. G. ́. (2014) · Cited by 51
Padilha, C. S., Figueiredo, C., Minuzzi, L. G., Chimin, P., Deminice, R., Krüger, K., Neto, J. C. R., & Lira, F. S. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101341 · Cited by 54
Hypoxia Signaling in Parkinson’s Disease: There Is Use in Asking “What HIF?”
Pinilla, L. L., Ugun‐Klusek, A., Rutella, S., & Girolamo, L. A. D. (2021) · Biology · doi:10.3390/biology10080723 · Cited by 52
“activity, producing succinate as by-product [17].”
Hypoxia-Inducible Factor Regulates Endothelial Metabolism in Cardiovascular Disease
Ullah, K., & Wu, R. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.670653 · Cited by 50
“Angiopoietins are required for remodeling the vascular plexus, while VEGF induces EC proliferation (Yancopoulos et al., 2000; Semenza, 2003) and glycolytic flux (Fraisl et al., 2009; De Bock et al., 2013), which facilitates the sprouting of new capillaries (Shweiki et al., 1992; Liu et al., 1995).”
BackgroundZhang, Q., Sun, W., Li, T., & Liu, F. (2023) · Journal of Inflammation Research · doi:10.2147/jir.s401968 · Cited by 50
“71,89,90 Meanwhile, the increased content of the TCA cycle intermediate succinate could be transported from the mitochondria into the cytosol and impair the activity of prolyl hydroxylases (PDH), which further facilitates the stabilization and production of HIF1α.91 This event induced by excessive succinate has been d…”
BackgroundInfluentialMarden, J. H., Fescemyer, H. W., Schilder, R. J., Doerfler, W. R., Vera, J. C., & Wheat, C. W. (2012) · Evolution · doi:10.1111/evo.12004 · Cited by 49
Barliya, T., Mandel, M., Livnat, T., Weinberger, D., & Lavie, G. (2011) · PLoS ONE · doi:10.1371/journal.pone.0022849 · Cited by 50
“[9], mutations in mitochondrial succinic dehydrogenases in paraganglioma, and others [10].”
BackgroundCuezva, J. M., Sánchez‐Aragó, M., Sala, S., Blanco-Rivero, A., & Ortega, A. D. (2007) · Journal of Bioenergetics and Biomembranes · doi:10.1007/s10863-007-9087-9 · Cited by 51
Womeldorff, M. R., Gillespie, D. L., & Jensen, R. L. (2014) · Neurosurgical FOCUS · doi:10.3171/2014.9.focus14496 · Cited by 51
Actuality of Warburg’s views in our understanding of renal cancer metabolism
Godinot, C., de Laplanche, E., Hervouet, É., & Simonnet, H. (2007) · Journal of Bioenergetics and Biomembranes · doi:10.1007/s10863-007-9088-8 · Cited by 49
“In these types of cancers, the increase in succinate level is accompanied by an increase of HIF, likely through a feedback inhibition of PHD ( Selak et al. 2005 ), although this is still being”
BackgroundHsu, C., Wang, C.-H., Wu, L.-C., Hsia, C., Chi, C., Yin, P., Chang, C.-J., Sung, M., Wei, Y., Lu, S.-H., et al. (2013) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2013.06.004 · Cited by 50
“Moreover, mitochondrial generated reactive oxygen species (ROS) [7,8] or released metabolite succinate [9] might inhibit the protein degradation of HIF-1α.”
BackgroundHouston, M. A., Augenlicht, L. H., & Heerdt, B. G. (2011) · International Journal of Cell Biology · doi:10.1155/2011/978583 · Cited by 50
“Pseudohypoxia is achieved by either defective TCA cyclemediated impaired degradation of HIF1α or by accelerated mTOR-mediated translation of HIF1α [54–57].”
BackgroundChupani, L., Niksirat, H., Lünsmann, V., Haange, S., von Bergen�, M., Jehmlich, N., & Zusková, E. (2017) · The Science of The Total Environment · doi:10.1016/j.scitotenv.2017.08.129 · Cited by 49
Glycolysis Inhibition as a Strategy for Hepatocellular Carcinoma Treatment?
Alves, Â., Mamede, A. C., Alves, M. G., Oliveira, P. F., Rocha, S. M., Botelho, M. F., & Maia, C. J. (2018) · Current Cancer Drug Targets · doi:10.2174/1568009618666180430144441 · Cited by 50
Piantadosi, C. A., & Suliman, H. B. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m709741200 · Cited by 50
Mailloux, R. J., & Appanna, V. D. (2006) · Toxicology in Vitro · doi:10.1016/j.tiv.2006.07.013 · Cited by 50
Ziebart, T., Walenta, S., Kunkel, M., Reichert, T. E., Wagner, W., & Mueller‐Klieser, W. (2010) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-010-0875-y · Cited by 50
“as well as defects in the Krebs cycle (Gottlieb and Tomlinson 2005; Isaacs et al. 2005; Selak et al. 2005).”
BackgroundLocasale, J. W., Cantley, L. C., & Heiden, M. G. V. (2009) · Nature Biotechnology · doi:10.1038/nbt1009-916 · Cited by 51
Metabolic Alterations in Cancer and Their Potential as Therapeutic Targets
Weyandt, J. D., Thompson, C. B., Giaccia, A. J., & Rathmell, W. K. (2017) · American Society of Clinical Oncology Educational Book · doi:10.1200/edbk_175561 · Cited by 77
Self-citationWenger, R. H., & Kurtz, A. (2011) · Comprehensive physiology · doi:10.1002/cphy.c100075 · Cited by 55
Iverson, T. M., Singh, P. K., & Cecchini, G. (2023) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2023.104761 · Cited by 57
“Thus, the accumulation of cellular succinate and increase of the cellular succinate:α-ketoglutarate ratio in cells following the reduction, loss, or reversal of complex II activity can inhibit PHD2, stabilize HIF1α, shift metabolism toward aerobic glycolysis (18), and induce cytokines and inflammation (182).”
BackgroundSun, G., Zhao, S., Fan, Z., Wang, Y., Liu, H., Cao, H., Sun, G., Huang, T., Cai, H., Pan, H., et al. (2023) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-023-02803-0 · Cited by 47
“Defects in SDH in cancer cells lead to abnormal accumulation of succinate in the mitochondria and cytoplasm [14].”
BackgroundMitochondrial diseases and the role of the yeast models
Rinaldi, T., Dallabona, C., Ferrero, I., Frontali, L., & Bolotin‐Fukuhara, M. (2010) · FEMS Yeast Research · doi:10.1111/j.1567-1364.2010.00685.x · Cited by 49
Shimizu, T., Inoue, K.-I., Hachiya, H., Shibuya, N., Shimoda, M., & Kubota, K. (2013) · Journal of Gastroenterology · doi:10.1007/s00535-013-0895-x · Cited by 47
“SDHB is a tumor suppressor of familial paraganglioma or pheochromocytoma [15, 16], and loss of its function leads to succinate accumulation [17].”
BackgroundSensitivity of hematopoietic stem cells to mitochondrial dysfunction by SdhD gene deletion
Bejarano-García, J. A., Millán‐Uclés, Á., Rosado, I. V., Sánchez‐Abarca, L. I., Caballero‐Velázquez, T., Durán-Galván, M. J., Pérez‐Simón, J. A., & Piruat, J. I. (2016) · Cell Death and Disease · doi:10.1038/cddis.2016.411 · Cited by 54
“27,30,47 Hif1 α has proven to have a crucial role in the maintenance of the quiescent stage as well as in the stress resistance of these cells.”
Qian, L., Zhao, A., Zhang, Y., Chen, T., Zeisel, S. H., Jia, W. P., & Cai, W. (2016) · International Journal of Molecular Sciences · doi:10.3390/ijms17122128 · Cited by 49
Exploring Non-Metabolic Functions of Glycolytic Enzymes in Immunity
Seki, S. M., & Gaultier, A. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01549 · Cited by 49
Immunometabolism: A new target for improving cancer immunotherapy
Guo, C., Chen, S., Liu, W., Ma, Y., Li, J., Fisher, P. B., Fang, X., & Wang, X. (2019) · Advances in cancer research · doi:10.1016/bs.acr.2019.03.004 · Cited by 56
“Mutations of SDH or FH also appear to inhibit PHD activity via abnormal accumulation of succinate or fumarate (Isaacs et al., 2005; Selak et al., 2005).”
BackgroundJeske, R., Yuan, X., Fu, Q., Bunnell, B. A., Logan, T. M., & Li, Y. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.621744 · Cited by 49
“For instance, succinate was found to accumulate in M1 polarized macrophages (74).”
BackgroundDahia, P. L. M. (2006) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1353.023 · Cited by 50
Mitochondrial DNA Mutations in Cancer
Zanssen, S., & Schon, E. A. (2005) · PLoS Medicine · doi:10.1371/journal.pmed.0020401 · Cited by 47
Bénit, P., Goncalves, J., El‐Khoury, R., Rak, M., Favier, J., Gimenez‐Roqueplo, A., & Rustin, P. (2022) · Biomedicines · doi:10.3390/biomedicines10081788 · Cited by 49
Hix, L. M., Frey, D. A., McLaws, M. D., et al. (2005) · Carcinogenesis · doi:10.1093/carcin/bgi121 · Cited by 47
The role of HIFs in ischemia-reperfusion injury
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Proline-Hydroxylated Hypoxia-Inducible Factor 1α (HIF-1α) Upregulation in Human Tumours
Snell, C. E., Turley, H., McIntyre, A., Li, D., Masiero, M., Schofield, C. J., Gatter, K. C., Harris, A. L., & Pezzella, F. (2014) · PLoS ONE · doi:10.1371/journal.pone.0088955 · Cited by 49
Seyfried, T. N., Mukherjee, P., İyikesici, M. S., Slocum, A. K., Kalamian, M., Spinosa, J., & Chinopoulos, C. (2020) · Frontiers in Nutrition · doi:10.3389/fnut.2020.00021 · Cited by 49
Metabolite regulation of epigenetics in cancer
Wang, P., Chen, L., Xiong, Y., & Ye, D. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114815 · Cited by 50
Mitochondrial Alterations During Carcinogenesis
Wang, X., Peralta, S., & Moraes, C. T. (2013) · Advances in cancer research · doi:10.1016/b978-0-12-407190-2.00004-6 · Cited by 47
Pfeiffer, M. E., Kayzer, E.-B., Yang, X., Abramson, E. M., Kenaston, M. A., Lago, C. U., Lo, H.-H., Sedensky, M. M., Lunceford, A. L., Clarke, C. F., et al. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.271452 · Cited by 46
Zhang, Y., Zhang, Z., Zhao, Y., Cheng, S., & Ren, H. (2013) · Environmental Science & Technology · doi:10.1021/es3048976 · Cited by 46
Lemarié, A., & Grimm, S. (2009) · Mitochondrion · doi:10.1016/j.mito.2009.03.004 · Cited by 45
“This and the recent findings linking complex II mutations to Hypoxia InducibleFactor-1 could explain, amongst others, why some of its subunits have been proposed to constitute tumour suppressors in a range of different cancers (Baysal et al., 2000; Gottlieb and Tomlinson, 2005; Niemann and Muller, 2000; Selak et al.,…”
BackgroundLemire, J. A., Mailloux, R. J., Darwich, R., Auger, C., & Appanna, V. D. (2011) · Toxicology Letters · doi:10.1016/j.toxlet.2011.03.019 · Cited by 46
Mitonuclear Interactions Mediate Transcriptional Responses to Hypoxia inDrosophila
Mossman, J. A., Tross, J. G., Jourjine, N. A., Li, N., Wu, Z. J., & Rand, D. M. (2016) · Molecular Biology and Evolution · doi:10.1093/molbev/msw246 · Cited by 50
“Succinate dehydrogenase is a tumor suppressor found in complex II in mitochondria (Selak et al. 2005) and is suspected as being involved in the pseudohypoxic response that enhances glycolysis (King et al. 2006).”
BackgroundRescue of TCA Cycle Dysfunction for Cancer Therapy
Marquez, J. C., Flores, J., Kim, A. H., Nyamaa, B., Nguyen, A. T. T., Park, N., & Han, J. (2019) · Journal of Clinical Medicine · doi:10.3390/jcm8122161 · Cited by 47
“The SDH complex consists of four subunits (SDHA, SDHB, SDHC, and SDHD), and a deficiency of this enzyme is known to activate tumor formation through dysregulation of HIF activity [52].”
BackgroundYin, L., Zhang, Y., Wu, H., et al. (2020) · LWT · doi:10.1016/j.lwt.2020.110087 · Cited by 46
Host-Directed Therapy in Tuberculosis: Targeting Host Metabolism
Kim, J., Kim, Y.-R., & Yang, C. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01790 · Cited by 47
“the production of anti-inflammatory cytokines, and enhances HIF-1α activity by inhibiting HIF-1α prolyl hydrolases [72-74].”
BackgroundGarcia-Rojas, E. Y. L., Villanueva, C., & Bond, R. A. (2021) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2021.709509 · Cited by 49
“Under the metabolic switch during infection, accumulation of the TCA cycle intermediate, succinate, is transported to the cytoplasm and stabilizes HIF-1α (106, 107).”
BackgroundMetabolic reprogramming: A novel therapeutic target in diabetic kidney disease
Wang, M., Pang, Y., Guo, Y., Tian, L., Liu, Y., Shen, C., Liu, M., Meng, Y., Cai, Z., Wang, Y., et al. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.970601 · Cited by 47
Metabolomics-Based Identification of Metabolic Dysfunction in Frailty
Westbrook, R., Zhang, C., Yang, H., Tian, J., Guo, S., Xue, Q., Walston, J. D., Le, A., & Abadir, P. M. (2021) · The Journals of Gerontology Series A · doi:10.1093/gerona/glab315 · Cited by 49
Inflammation driven metabolic regulation and adaptation in macrophages
Gupta, S., & Sarangi, P. P. (2022) · Clinical Immunology · doi:10.1016/j.clim.2022.109216 · Cited by 46
Xu, J., Yang, Y., Li, X., Ding, S., Zheng, L., Xiong, C., & Yang, Y. (2023) · iMeta · doi:10.1002/imt2.124 · Cited by 47
“The accumulation of succinate has been found to instigate the growth and invasion of smooth muscle cells (SMCs) into the intima, a phenomenon observed in atherosclerosis [79].”
BackgroundExtracellular Succinate: A Physiological Messenger and a Pathological Trigger
Wu, K. K. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241311165 · Cited by 48
Metabolomic Profiling Reveals a Role for Caspase-2 in Lipoapoptosis
Johnson, E. S., Lindblom, K., Robeson, A. C., Stevens, R. D., Ilkayeva, O., Newgard, C. B., Kornbluth, S. A., & Andersen, J. L. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.437210 · Cited by 45
Hou, P., Kuo, C., Cheng, C.-T., Liou, J., Ann, D. K., & Chen, Q. (2014) · PLoS ONE · doi:10.1371/journal.pone.0113865 · Cited by 46
“Mutations in SDH or FH are found in cancers and cause succinate or fumarate to accumulate and compete with a-KG for PHD binding, thereby inhibiting PHD and stabilizing HIF-1a [12,13].”
BackgroundInfluentialDu, C., Kurabe, N., Matsushima, Y., Suzuki, M., Kahyo, T., Ohnishi, I., Tanioka, F., Tajima, S., Goto, M., Yamada, H., et al. (2014) · Gastric Cancer · doi:10.1007/s10120-014-0409-4 · Cited by 46
“dependent dioxygenases, particularly hypoxia-inducible factor (HIF) prolyl hydroxylases [29, 30] and the JmjC domain containing histone demethylases [31].”
BackgroundWang, J. H., Lasota, J. P., & Miettinen, M. (2011) · Journal of Cancer · doi:10.7150/jca.2.90 · Cited by 45
“It is believed that loss of SDHB expression leads to a tumorigennic mechanism involving the stabilization of Hypoxia Inducing Factors (HIF), which in turn upregulates genes that promote adaptation of cells in low-oxygen environments by inducing angiogenesis and glycolysis [17-20].”
BackgroundMiguel, M. P., Alcaina, Y., de la Maza, D. S., & López-Iglesias, P. (2015) · Current Molecular Medicine · doi:10.2174/1566524015666150505160406 · Cited by 47
“Low levels of succinate dehydrogenase and fumarase, mitochondrial enzymes of the respiratory chain and the tricarboxylic acid (TCA) cycle respectively, have been linked to stabilization of HIF1α under normoxic conditions [63,64], and the glucose metabolites pyruvate and oxaloacetate inhibit HIF1α protein degradation […”
BackgroundStudies of Secondary Melanoma on C57BL/6J Mouse Liver Using 1H NMR Metabolomics
Feng, J., Isern, N., Burton, S., & Hu, J. Z. (2013) · Metabolites · doi:10.3390/metabo3041011 · Cited by 45
“The significance of this finding has not been fully elucidated, but the genes encoding succinate dehydrogenase (SDH) and fumarate hydratase (FH) are thought to be major tumor suppressor genes [61,62].”
BackgroundCancer morphogenesis: role of mitochondrial failure.
Fosslien, E. (2008) · PubMed · Cited by 45
Charville, G. W., & Longacre, T. A. (2017) · Advances in Anatomic Pathology · doi:10.1097/pap.0000000000000166 · Cited by 45
Aldera, A. P., & Govender, D. (2017) · Journal of Clinical Pathology · doi:10.1136/jclinpath-2017-204677 · Cited by 46
Badur, M. G., & Metallo, C. M. (2017) · Metabolic Engineering · doi:10.1016/j.ymben.2017.11.013 · Cited by 44
“These loss-of-function mutations lead to increases in succinate or fumarate levels within tumors, which are thought to inhibit aKGdependent dioxygenases that impact HIF1α stabilization and other biological processes (MacKenzie et al., 2007; Selak et al., 2005; Xiao et al., 2012).”
BackgroundShen, J., Wang, C., Ying, J., Xu, T., McAlinden, A., & O’Keefe, R. J. (2019) · JCI Insight · doi:10.1172/jci.insight.128568 · Cited by 46
Muscle-Liver Substrate Fluxes in Exercising Humans and Potential Effects on Hepatic Metabolism
Hu, C., Hoene, M., Plomgaard, P., Hansen, J. S., Zhao, X., Li, J., Wang, X., Clemmesen, J. O., Secher, N. H., Häring, H. U., et al. (2019) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgz266 · Cited by 44
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Holzner, L. M. W., & Murray, A. J. (2021) · Frontiers in Medicine · doi:10.3389/fmed.2021.753268 · Cited by 45
“HIF activation can also result from succinate accumulation (20).”
BackgroundRecent advances in understanding the metabolic plasticity of ovarian cancer: A systematic review
Kobayashi, H. (2022) · Heliyon · doi:10.1016/j.heliyon.2022.e11487 · Cited by 46
The power of yeast to model diseases of the powerhouse of the cell
Claypool, S. M. (2012) · Frontiers in bioscience · doi:10.2741/4098 · Cited by 42
“Cytosolic succinate can then act as an inhibitor of alpha-ketoglutarate-dependent enzymes including prolyl hydroxylases that normally facilitate the rapid ubiquitindependent removal of HIF-1 alpha (233).”
BackgroundMitochondrial complex II and genomic imprinting in inheritance of paraganglioma tumors
Baysal, B. E. (2013) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2012.12.005 · Cited by 44
“Despite these observations, role of mitochondrial complex II in oxygen sensing and signaling pathways remains poorly understood, although both succinate [40] and ROS [31] were implicated as downstream messengers that activate hypoxia-inducible pathways.”
Targeting metabolic pathways for head and neck cancers therapeutics
Yamamoto, M., Inohara, H., & Nakagawa, T. (2017) · Cancer and Metastasis Reviews · doi:10.1007/s10555-017-9691-z · Cited by 44
Role of coenzymes in cancer metabolism
Thapa, M., & Dallmann, G. (2019) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2019.05.027 · Cited by 45
Targeting immunometabolism to treat COVID-19
O’Carroll, S. M., & O'Neill, L. A. J. (2021) · Immunotherapy Advances · doi:10.1093/immadv/ltab013 · Cited by 44
“Succinate accumulation also causes reverse electron transport (RET) causing mtROS production and the stabilisation of HIF1α [4, 5].”
BackgroundLee, T.-Y., Muschal, S., Pravda, E. A., Folkman, J., Abdollahi, A., & Javaherian, K. (2009) · Blood · doi:10.1182/blood-2008-12-197236 · Cited by 47
TRAP1 Chaperones the Metabolic Switch in Cancer
Wengert, L. A., Backe, S. J., Bourboulia, D., Mollapour, M., & Woodford, M. R. (2022) · Biomolecules · doi:10.3390/biom12060786 · Cited by 45
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“In case of underlying mutations of the mitochondrial enzyme SDH, succinate accumulation inhibits prolyl hydroxylase activity and consequently HIFa stabilization (Selak et al. 2005).”
BackgroundAnalyzing Tumor Metabolism In Vivo
Faubert, B., & DeBerardinis, R. J. (2016) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-050216-121954 · Cited by 44
“These dioxygenases include histone demethylases, 5-methylcytosine hydroxylases, and prolyl hydroxylases that target hypoxia-inducible factor-α subunits for degradation (Isaacs et al. 2005, Letouze et al. 2013, Sciacovelli et al. 2016, Selak et al. 2005, Xiao et al. 2012).”
BackgroundMolecular markers of paragangliomas/pheochromocytomas
Zhikrivetskaya, S. O., Snezhkina, A. V., Zaretsky, A. R., Alekseev, B. Y., Pokrovsky, A. V., Golovyuk, A. L., Melnikova, N. V., Stepanov, O. A., Kalinin, D. V., Moskalev, A., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.15201 · Cited by 45
“The ROS level is elevated in cells with mutant FH [101], whereas data on ROS concentration in SDH-mutant cells are contradictory [95, 102-104].”
BackgroundZhou, Z., Ibekwe, E., & Chornenkyy, Y. (2018) · Antioxidants · doi:10.3390/antiox7010016 · Cited by 44
“Similarly to 2 HG, high levels of succinate accumulate and leak out of the mitochondria via the dicarboxylate carrier and inhibit activity of HIFα PHDs in the cytosol, creating high levels of HIF1α and inducing a pseudohypoxic response [117].”
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Role of Sirtuins in Tumor Angiogenesis
Edatt, L., Poyyakkara, A., Raji, G. R., Ramachandran, V., Shankar, S. S., & Kumar, V. B. S. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2019.01516 · Cited by 43
Multifaceted Actions of Succinate as a Signaling Transmitter Vary with Its Cellular Locations
Guo, Y., Cho, S. W., Saxena, D. B., & Li, X. (2020) · Endocrinology and Metabolism · doi:10.3803/enm.2020.35.1.36 · Cited by 44
“Cytosolic succinate inhibits HIF-α prolyl hydroxylase, and activities and protects HIF-1α degradation [76].”
BackgroundBruno, S., Mancini, M., Santis, S. D., Monaldi, C., Cavo, M., & Soverini, S. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22136857 · Cited by 43
“Both were identified as regulators of some HIF targets via ten-eleven translocation (TET) inhibition [82] and as inhibitors of PHDs [83,84], suggesting a role in the maintenance of hypoxia response as well as in histone and DNA demethylation.”
BackgroundInfluentialMetabolic Alterations in Cancer and Their Potential as Therapeutic Targets
Weyandt, J. D., Thompson, C. B., Giaccia, A. J., et al. (2017) · American Society of Clinical Oncology Educational Book · doi:10.14694/edbk_175561 · Cited by 42
Self-citationSuccinate at the Crossroad of Metabolism and Angiogenesis: Roles of SDH, HIF1α and SUCNR1
Atallah, R., Olschewski, A., & Heinemann, Á. (2022) · Biomedicines · doi:10.3390/biomedicines10123089 · Cited by 43
“An important consequence of succinate accumulation in the cytosol is the inhibition of prolyl hydroxylase (PHD) [30].”
BackgroundResultInfluentialGlutamine Metabolism: Molecular Regulation, Biological Functions, and Diseases
Kumar, M. A., Baba, S. K., Khan, I. R., Khan, M. S., Husain, F. M., Ahmad, S., Haris, M., Singh, M., Akil, A. A., Macha, M. A., et al. (2025) · MedComm · doi:10.1002/mco2.70120 · Cited by 52
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GPR91 deficiency exacerbates allergic contact dermatitis while reducing arthritic disease in mice
Rubic-Schneider, T., Carballido‐Perrig, N., Regairaz, C., Raad, L., Jost, S., Rauld, C., Christen, B., Wieczorek, G., Kreutzer, R., Dawson, J., et al. (2016) · Allergy · doi:10.1111/all.13005 · Cited by 43
“Succinate inhibits hypoxia-inducible factor-1a (HIF-1a) prolyl hydroxylase and therefore stabilizes HIF-1a (37), which in turns enhances IL-1b production.”
BackgroundThe use of hyperpolarized carbon-13 magnetic resonance for molecular imaging
Siddiqui, S. M., Kadlecek, S. J., Pourfathi, M., Xin, Y., Mannherz, W. P., Hamedani, H., Drachman, N., Ruppert, K., Clapp, J. T., & Rizi, R. R. (2016) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2016.08.011 · Cited by 42
“ability to image the fate of succinate would provide insights into many pathologies that affect oxidative phosphorylation [196,197], especially”
Tarhonskaya, H., Nowak, R. P., Johansson, C., Szykowska, A., Tumber, A., Hancock, R. L., Lang, P. A., Flashman, E., Oppermann, U. C. T., Schofield, C. J., et al. (2017) · Journal of Molecular Biology · doi:10.1016/j.jmb.2017.08.007 · Cited by 45
“2OG oxygenases by succinate, fumarate[20-24] or D-/L-2-hydroxyglutarate (D-/L-2HG),[25-27] including the histone demethylase KDM4A [28, 29].”
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Macrophage activation as an archetype of mitochondrial repurposing
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“Much like bioenergetics, early inspiration likely came from the field of cancer metabolism following the discovery that cancers linked to TCA cycle mutations accumulate metabolites that can alter transcription factor activation and epigenetic remodeling (Lu et al., 2012; Selak et al., 2005; Xiao et al., 2012; Xu et al…”
BackgroundThe VHL/HIF Axis in the Development and Treatment of Pheochromocytoma/Paraganglioma
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“Accumulated succinate can cross both the inner and outer mitochondrial membrane via the dicarboxylic acid transporter and the voltage-dependent anion channel (VDAC) [summarized in (12, 16)] to reach the cytosol.”
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Targeting fuel pocket of cancer cell metabolism: A focus on glutaminolysis
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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
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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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