Related Experiment Video

Updated: Aug 20, 2026

Functionalized Spirocyclic Heterocycle Synthesis and Cytotoxicity Assay
05:17

Functionalized Spirocyclic Heterocycle Synthesis and Cytotoxicity Assay

Published on: February 9, 2021

Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase

Mary A Selak1, Sean M Armour, Elaine D MacKenzie

  • 1Apoptosis and Tumour Physiology Laboratory, Beatson Institute for Cancer Research, Cancer Research UK Beatson Laboratories, Switchback Road, Glasgow G61 1BD, United Kingdom.

Cancer Cell
|January 18, 2005
PubMed

Insights

Mitochondrial succinate dehydrogenase (SDH) defects cause succinate buildup, activating HIF-1alpha. This links TCA cycle dysfunction to tumor formation and explains vascular tumors.

Area of Science:

  • Biochemistry
  • Oncology
  • Cellular Biology

Background:

  • Mitochondrial proteins like succinate dehydrogenase (SDH) and fumarate hydratase are known tumor suppressors.
  • These enzymes are crucial components of the tricarboxylic acid (TCA) cycle.
  • The precise mechanisms linking TCA cycle defects to tumor development remain unclear.

Purpose of the Study:

  • To elucidate the signaling pathway connecting mitochondrial dysfunction to oncogenic events.
  • To investigate the role of succinate accumulation in tumor formation.
  • To explain the development of highly vascular tumors in the context of SDH mutations.

Main Methods:

  • Describing a novel mitochondrion-to-cytosol signaling pathway.
  • Analyzing the effects of SDH inhibition and succinate accumulation.
  • Investigating the inhibition of HIF-alpha prolyl hydroxylases by succinate.
  • Examining the stabilization and activation of HIF-1alpha.

Main Results:

  • Succinate accumulates due to SDH inhibition.
  • Accumulated succinate inhibits cytosolic HIF-alpha prolyl hydroxylases.
  • HIF-1alpha is stabilized and activated.
  • A mechanistic link between SDH mutations and HIF-1alpha induction is established.

Conclusions:

  • Mitochondrial dysfunction, specifically SDH defects, can drive oncogenesis through a mitochondrion-to-cytosol signaling pathway.
  • The pathway involves succinate-mediated inhibition of HIF-alpha prolyl hydroxylases, leading to HIF-1alpha activation.
  • This provides a molecular explanation for the angiogenesis observed in tumors with SDH mutations, even without VHL mutations.

More Related Videos

Synthesis and Characterization of an Aspirin-fumarate Prodrug that Inhibits NFκB Activity and Breast Cancer Stem Cells13:38

Synthesis and Characterization of an Aspirin-fumarate Prodrug that Inhibits NFκB Activity and Breast Cancer Stem Cells

Published on: January 18, 2017

Related Concept Videos

Electron Transport Chain: Complex I and II01:46

Electron Transport Chain: Complex I and II

The mitochondrial electron transport chain (ETC) is the main energy generation system in the eukaryotic cells. However, mitochondria also produce cytotoxic reactive oxygen species (ROS) due to the large electron flow during oxidative phosphorylation. While Complex I is one of the primary sources of superoxide radicals, ROS production by Complex II is uncommon and may only be observed in cancer cells with mutated complexes.
ROS generation is regulated and maintained at moderate levels necessary...
Allosteric Proteins-ATCase01:19

Allosteric Proteins-ATCase

Binding sites linkages can regulate a protein's function.  For example, enzyme activity is often regulated through a feedback mechanism where the end product of the biochemical process serves as an inhibitor.
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to  N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis pathway,...
ATP Synthase: Mechanism01:48

ATP Synthase: Mechanism

In animals, the mitochondrial F1F0 ATP synthase is the key protein that synthesizes ATP molecules through a complex catalytic mechanism. While the nuclear genome encodes the majority of ATP synthase subunits, the mitochondrial genome encodes some of the enzyme's most critical components. The formation of this multi-subunit enzyme is a complex multi-step process regulated at the level of transcription, translation, and assembly. Defects in one or more of these steps can result in decreased ATP...
Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
Phase II Reactions: Miscellaneous Conjugation Reactions01:19

Phase II Reactions: Miscellaneous Conjugation Reactions

Phase II biotransformations are detoxification mechanisms that conjugate xenobiotics with endogenous substances, neutralizing their toxicity.
A key example involves the conjugation of cyanide ions, which impair cellular respiration and alter hemoglobin into non-oxygen-carrying cyanmethemoglobin. To neutralize this threat, a sulfur atom from thiosulphate is transferred to the cyanide ion, catalyzed by the enzyme rhodanese, resulting in an inactive compound called thiocyanate. The production of...
Cancer-Critical Genes II: Tumor Suppressor Genes01:05

Cancer-Critical Genes II: Tumor Suppressor Genes

Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern, thereby altering the phenotype.
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...