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Related Concept Videos

The Citric Acid Cycle: Output01:28

The Citric Acid Cycle: Output

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The citric acid cycle is termed an amphibolic pathway as it operates both anabolically and catabolically. The cyclic reactions balance the flux of the substrates to provide an optimal concentration of NADH and ATP to the cell.
Regulation of Citric Acid Cycle
The citric acid cycle is regulated in several ways, including feedback inhibition, regulation of enzyme activities, and associated anaplerotic or cataplerotic pathways.
The primary substrate of the TCA cycle—acetyl CoA—is...
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The Citric Acid Cycle: Overview01:37

The Citric Acid Cycle: Overview

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In aerobic organisms, the citric acid cycle is the second stage of cellular respiration wherein molecules derived from the breakdown of carbohydrates, proteins, and fats are oxidized into carbon dioxide and energy. This process is also known as the tricarboxylic acid (TCA) cycle as the first product of the cycle, citric acid, contains three carboxyl groups in its structure. Alternatively, this cycle is also referred to as the Krebs cycle, in honor of its discoverer Sir Hans Krebs.
The citric...
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The Citric Acid Cycle02:36

The Citric Acid Cycle

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The citric acid cycle, also known as the Krebs cycle or TCA cycle, consists of several energy-generating reactions that yield one ATP molecule, three NADH molecules, one FADH2 molecule, and two CO2 molecules.
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Electron Transport Chain: Complex I and II01:46

Electron Transport Chain: Complex I and II

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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...
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Tumor Progression02:07

Tumor Progression

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Tumor progression is a phenomenon where the pre-formed tumor acquires successive mutations to become clinically more aggressive and malignant. In the 1950s, Foulds first described the stepwise progression of cancer cells through successive stages.
Colon cancer is one of the best-documented examples of tumor progression. Early mutation in the APC gene in colon cells causes a small growth on the colon wall called a polyp. With time, this polyp grows into a benign, pre-cancerous tumor. Further...
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Products of the Citric Acid Cycle00:53

Products of the Citric Acid Cycle

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The cells of most organisms—including plants and animals—obtain usable energy through aerobic respiration, the oxygen-requiring version of cellular respiration. Aerobic respiration consists of four major stages: glycolysis, pyruvate oxidation, the citric acid cycle, and oxidative phosphorylation. The third major stage, the citric acid cycle, is also known as the Krebs cycle or tricarboxylic acid (TCA) cycle.
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Related Experiment Video

Updated: Sep 9, 2025

In vitro Organoid Culture of Primary Mouse Colon Tumors
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A Citrate Synthase Splice Variant Rewires the TCA Cycle to Promote Colorectal Cancer Progression.

Justin Chak Ting Cheung1, Lok Wan Ng2, Zhongxu Zhu3,4

  • 1Department of Surgery, Sir Yue-Kong Pao Centre for Cancer, The Chinese University of Hong Kong, Shatin, N. T., Hong Kong SAR, China.

Cancer Research
|September 3, 2025
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A newly discovered citrate synthase (CS) splicing variant, CS-ΔEx4, drives colorectal cancer (CRC) progression by altering the tricarboxylic acid (TCA) cycle. Targeting this variant shows promise for CRC therapy.

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Deficient Pms2, ERCC1, Ku86, CcOI in Field Defects During Progression to Colon Cancer
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Area of Science:

  • Cancer Biology
  • Metabolic Reprogramming
  • Molecular Oncology

Background:

  • Metabolic reprogramming, particularly tricarboxylic acid (TCA) cycle alterations, is a key feature of cancer supporting tumor growth and metastasis.
  • The precise mechanisms of TCA cycle rewiring in colorectal carcinogenesis remain incompletely understood.

Purpose of the Study:

  • To identify and characterize novel mechanisms of TCA cycle dysregulation in colorectal cancer (CRC).
  • To investigate the role of a specific citrate synthase (CS) splicing isoform, CS-ΔEx4, in CRC progression.

Main Methods:

  • Identification and quantification of CS splicing isoforms (CS-ΔEx4 and CS-FL) in CRC tumors.
  • Clinical correlation analysis of CS-ΔEx4 expression with patient outcomes.
  • In vitro and in vivo functional assays to assess CS-ΔEx4's role in CRC cell aggressiveness.
  • Mechanistic studies involving mitochondrial heterocomplex formation and metabolic flux analysis.
  • In silico screening for small molecules targeting the CS-ΔEx4/CS-FL heterocomplex.

Main Results:

  • CS-ΔEx4 was significantly upregulated in CRC tumors compared to the canonical CS-FL isoform.
  • Elevated CS-ΔEx4 expression correlated with increased cancer recurrence and poorer survival in CRC patients.
  • CS-ΔEx4 promoted aggressive CRC phenotypes, accelerated TCA cycle flux, and increased oncometabolite 2-hydroxyglutarate accumulation.
  • CS-ΔEx4-induced metabolic changes led to epigenomic alterations and upregulation of oncogenic gene signatures.
  • A novel small molecule selectively inhibited the CS-ΔEx4/CS-FL heterocomplex, showing anti-proliferative effects in CRC models.

Conclusions:

  • A novel spliced variant of citrate synthase, CS-ΔEx4, actively promotes colorectal cancer progression.
  • CS-ΔEx4 dysregulates the TCA cycle, leading to oncometabolite accumulation and oncogenic signaling.
  • Targeting the CS-ΔEx4/CS-FL heterocomplex represents a potential therapeutic strategy for colorectal cancer.