Overview of TCA Cycle: Metabolic pathway, Functions and Steps

Occurring within the mitochondrial matrix, the TCA cycle (alternatively termed the Krebs or citric acid cycle) serves as the biochemical nexus for aerobic energy production and precursor biosynthesis. This cyclic pathway oxidizes acetyl-CoA to yield ATP-equivalent reducing agents (NADH, FADH₂), carbon dioxide, and metabolic intermediates for anabolic processes. Our analysis systematically examines its enzymatic reactions, regulatory networks, physiological roles, and clinical relevance.

Principle

The TCA cycle operates as a central metabolic hub, oxidizing acetyl-CoA—derived from carbohydrates, lipids, and proteins—into carbon dioxide. Concurrently, it produces reducing equivalents (NADH, FADH₂) and nucleotide triphosphates (ATP/GTP), coupling energy provision with the supply of biosynthetic precursors. This cyclical pathway comprises five functionally linked phases:

1. Acetyl-CoA Formation

The cycle initiates with Acetyl-CoA, primarily derived from:

• Pyruvate oxidation: Glycolytic pyruvate undergoes mitochondrial decarboxylation via the pyruvate dehydrogenase complex.
• β-Oxidation: Fatty acid catabolism generates acetyl groups for CoA conjugation.

2. Citrate Synthesis

Citrate synthase catalyzes the condensation of Acetyl-CoA and oxaloacetate (C₄), forming citrate (C₆). This irreversible reaction commits carbon substrates to oxidative metabolism.

3. Sequential Oxidative Decarboxylations

• Isocitrate to α-Ketoglutarate: Isocitrate dehydrogenase mediates NAD⁺-dependent oxidation, releasing CO₂ and producing NADH.
• α-Ketoglutarate to Succinyl-CoA: The α-ketoglutarate dehydrogenase complex facilitates a second decarboxylation, yielding additional NADH and CO₂.

4. Substrate-Level Phosphorylation

Succinyl-CoA synthetase converts thioester bond energy into GTP/ATP through direct phosphate transfer, bypassing electron transport chain (ETC) dependency.

5. Electron Carrier Generation and Cycle Renewal

• Succinate to Oxaloacetate: Subsequent oxidations (succinate → fumarate → malate) regenerate NADH and FADH₂, which feed electrons into the ETC.
• Oxaloacetate Regeneration: Malate dehydrogenase produces oxaloacetate, completing the cycle for subsequent Acetyl-CoA entry.

The TCA cycle with all intermediates (in black), by-products (in green), and enzymes (in red) (Judge A et al., 2020).

Reaction Cascade Overview

1. Acetyl-CoA and Oxaloacetate Condensation

• Reaction: Acetyl-CoA + Oxaloacetate → Citrate + CoA-SH
• Catalyst: Citrate synthase (allosterically inhibited by ATP, NADH, succinyl-CoA)
• Mechanism: Irreversible aldol condensation of acetyl and α-keto groups
• Rate Limitation: Oxaloacetate availability sustained via anaplerotic pathways

2. Citrate Isomerization

• Reaction: Citrate ⇌ Isocitrate
• Catalyst: Aconitase (Fe-S cluster-dependent)
• Process: Sequential dehydration-hydration via cis-aconitate intermediate
• Vulnerability: Fe-S center susceptible to ROS-mediated inactivation

3. Isocitrate Oxidation/Decarboxylation

• Reaction: Isocitrate + NAD⁺ → α-Ketoglutarate + CO₂ + NADH
• Catalyst: Isocitrate dehydrogenase (IDH; activated by ADP, inhibited by ATP/NADH)
• Regulatory Node: Primary flux control point in the cycle

4. α-Ketoglutarate Conversion to Succinyl-CoA

• Reaction: α-KG + NAD⁺ + CoA → Succinyl-CoA + CO₂ + NADH
• Catalyst: α-KGDH complex (TPP, lipoate, FAD-dependent)
• Inhibition: Feedback suppression by succinyl-CoA/NADH; arsenic toxicity targets lipoamide

5. Succinyl-CoA Thioester Utilization

• Reaction: Succinyl-CoA + GDP → Succinate + GTP (animals)
• Catalyst: Succinyl-CoA synthetase (substrate-level phosphorylation)
• Bioenergetics: Direct GTP/ATP synthesis bypassing electron transport

6. Succinate Dehydrogenation

• Reaction: Succinate + FAD → Fumarate + FADH₂
• Catalyst: Succinate dehydrogenase (Complex II; membrane-bound ETC component)
• Inhibitor: Malonate mimics succinate structure (Ki = 0.1 mM)

7. Fumarate Hydration

• Reaction: Fumarate + H₂O → L-Malate
• Catalyst: Fumarase (stereospecific L-malate synthesis)

8. Malate Oxidation

• Reaction: Malate + NAD⁺ → Oxaloacetate + NADH
• Catalyst: Malate dehydrogenase (thermodynamically unfavorable; driven by oxaloacetate depletion)

For more detailed reaction process, please refer to "TCA Cycle Steps".

Amino Acid-Citric Acid Cycle Interplay (AACCI)

The biochemical interplay between amino acid metabolism and the TCA cycle constitutes a bidirectional metabolic exchange system. This framework enables amino acids to serve as both substrates for energy generation through conversion to TCA intermediates and precursors for biosynthetic pathways via cycle-derived metabolites. Such integration ensures cellular flexibility in nutrient utilization and macromolecule production.

Foundational Mechanisms of AACCI

Catabolic Entry Points

• Deamination Pathways: Amino acids undergo amino group removal via transamination or oxidative deamination, yielding α-keto acids structurally analogous to TCA intermediates (e.g., pyruvate → acetyl-CoA; glutamate → α-ketoglutarate).
• Anaplerotic Reactions: Resultant α-keto acids replenish cycle intermediates, sustaining TCA flux during fasting or prolonged exertion.

Anabolic Utilization

• Biosynthetic Precursors: TCA intermediates (oxaloacetate, α-ketoglutarate) serve as carbon skeletons for non-essential amino acid synthesis (e.g., aspartate, glutamine).
• Cataplerotic Diversion: Cycle metabolites exit to support gluconeogenesis, lipidogenesis, and nucleotide biosynthesis.

Key Amino Acid-TCA Nexus

• Alanine: Transaminates with α-ketoglutarate to form pyruvate, feeding into acetyl-CoA generation.
• Glutamate: Deaminated to α-ketoglutarate, directly entering the cycle's oxidative decarboxylation phase.
• Arginine/Proline: Metabolized to glutamate derivatives, ultimately yielding α-ketoglutarate or oxaloacetate.

Physiological Roles

Energy Homeostasis

• Mobilizes amino acid carbon skeletons as alternative catabolic fuel during carbohydrate depletion.
• Generates NADH/FADH₂ for oxidative phosphorylation via mitochondrial electron transport.

Metabolic Plasticity

• Supports nitrogen balance by coupling ammonia detoxification (urea cycle) with carbon skeleton utilization.
• Enables interconversion between glucogenic (e.g., alanine) and ketogenic (e.g., leucine) amino acids.

Biosynthetic Crossroads

Provides intermediates for:

• Glucose synthesis (via oxaloacetate → phosphoenolpyruvate)
• Lipid production (citrate → cytosolic acetyl-CoA)
• Heme/neurotransmitter formation (succinyl-CoA → δ-aminolevulinic acid)

Nitrogen Flux Coordination

• Ureagenesis Integration: Deamination-derived ammonia combines with aspartate (TCA-derived) in hepatic urea synthesis.
• Glutamate Shuttle: Facilitates amino group transfer between tissues while maintaining α-ketoglutarate/glutamate equilibrium.

Regulatory Architecture of the TCA Cycle

The tricarboxylic acid cycle is governed by a multifaceted control system integrating substrate availability, energy status, redox balance, and ionic signaling. This hierarchical regulation optimizes metabolic flux to align with cellular demands through modulation of enzymatic gatekeepers.

Central Regulatory Enzymes

Citrate Synthase

• Role: Catalyzes the condensation of acetyl-CoA and oxaloacetate, initiating cycle progression.
• Control Mechanisms: Substrate availability (oxaloacetate/acetyl-CoA levels) modulates catalytic efficiency. Product inhibition by citrate and ATP under energy-replete conditions.

Isocitrate Dehydrogenase (IDH)

• Function: Converts isocitrate to α-ketoglutarate while generating NAD(P)H.
• Regulatory Inputs: Subject to dual modulation by cellular energy charge (ATP/ADP ratio) and redox status (NADH/NAD⁺ balance). Calcium-mediated activation in excitable tissues.

α-Ketoglutarate Dehydrogenase (α-KGDH)

• Activity Profile: Inhibited by allosteric effectors (ATP, NADH) during high-energy states. Potentiated by Ca²⁺ influx during heightened ATP demand (e.g., muscle contraction).

Metabolic Modulators

Substrate Availability

• Acetyl-CoA Sources: Pyruvate dehydrogenase activity (glycolysis) or fatty acid β-oxidation.
• Oxaloacetate Dynamics: Cycle intermediates replenished via anaplerotic pathways (e.g., pyruvate carboxylation).

Energy Charge Sensing

• Elevated ATP/ADP ratios suppress IDH and α-KGDH, curbing NADH overproduction.
• ADP accumulation during energy deficit activates rate-limiting dehydrogenases.

Redox Homeostasis

• High NADH/NAD⁺ ratios inhibit IDH/α-KGDH, preventing reductive stress.
• Sustained electron transport chain (ETC) activity maintains NAD⁺ regeneration.

Calcium Signaling

In muscle and neurons, Ca²⁺ surges synchronize TCA flux with contractile/electrical activity by activating IDH and α-KGDH.

Regulatory Outcomes

• Energy Economy: Prevents futile cycling during nutrient abundance.
• Metabolic Flexibility: Prioritizes substrate utilization (glucose vs. fatty acids).
• Biosynthetic Balance: Adjusts precursor supply for anabolism vs. catabolism.

Physiological significance

Bioenergetic Output

The TCA cycle serves as a core metabolic pathway for cellular energy production, operating through dual mechanisms: direct substrate-level phosphorylation and indirect oxidative phosphorylation. This coordinated process ensures efficient ATP synthesis to meet cellular energy demands.

ATP Synthesis Mechanisms

• Substrate-Level Phosphorylation: During the cycle, one GTP (or ATP, depending on cell type) is directly generated through enzymatic transfer of a phosphate group, bypassing electron transport.
• Oxidative Phosphorylation: The majority of ATP derives from the oxidation of high-energy electron carriers (3 NADH and 1 FADH₂ per acetyl-CoA). These molecules transfer electrons to the mitochondrial electron transport chain (ETC), driving proton gradient formation and ATP synthase activation. Collectively, each acetyl-CoA oxidation yields ~10–12 ATP equivalents via ETC coupling.

Experimental studies reveal that pyruvate deficiency under hyperglycemic conditions impairs both glycolysis and TCA cycle activity, leading to ATP depletion and non-apoptotic Schwann cell death. Reduced pyruvate availability decreases flux through glycolysis, diminishing substrate input into the TCA cycle. Enzymes such as GAPDH and hexokinase exhibit reduced activity, exacerbating ATP deficits.Despite stable pyruvate dehydrogenase (PDH) activity, mitochondrial ATP production declines due to impaired cycle throughput.The ARP inhibitor Rucaparib mitigates cell death under pyruvate starvation but fails to restore TCA functionality. While glycolytic ATP production recovers partially, mitochondrial energy generation remains compromised (Yako H et al., 2024).

NADH and FADH₂ generation

The TCA cycle drives cellular energy production through the reduction of electron carriers. As substrates such as citrate and isocitrate undergo oxidation, they transfer high-energy electrons to NAD⁺ and FAD, forming NADH and FADH₂. These reduced coenzymes deliver electrons to the mitochondrial electron transport chain (ETC), where oxidative phosphorylation converts this redox potential into ATP. NADH-derived electrons contribute to approximately three ATP molecules per pair, while FADH₂ supports the synthesis of roughly two ATP molecules, establishing the TCA cycle as a cornerstone of cellular bioenergetics.

NNT, a mitochondrial enzyme, facilitates the interconversion of NADH and NADPH, linking catabolic and anabolic redox states. NNT suppression diminishes glutamine-driven TCA cycle activity, redirecting cells toward glucose catabolism. Isotopic tracing with [¹³C]-glucose and [¹³C]-glutamine demonstrated elevated glucose-derived metabolites in the TCA cycle, alongside increased glycolytic flux (evidenced by heightened glucose uptake and lactate secretion).Reduced NADPH/NADP⁺ ratios in NNT-deficient cells triggered compensatory activation of the pentose phosphate pathway (PPP) to sustain NADPH production.These cells exhibited impaired proliferation under glucose restriction, highlighting their reliance on glycolytic ATP. Enhanced NNT activity amplified both oxidative and reductive carboxylation of glutamine in the TCA cycle, improving cell viability in low-glucose environments. Elevated NADPH/NADP⁺ ratios correlated with metabolic resilience, though cells became susceptible to glutamine deprivation.NNT orchestrates a balance between NADH oxidation and NADPH synthesis, influencing cellular adaptation to nutrient availability. Its knockdown biases metabolism toward glucose oxidation while suppressing reductive carboxylation, whereas overexpression enhances glutamine-driven pathways. These findings underscore NNT's role in maintaining metabolic plasticity, particularly under nutrient stress, by modulating redox equilibria and substrate preference in central carbon metabolism (Gameiro PA ET AL., 2013).

Biosynthetic Precursors

In addition to energy production, intermediates in the TCA cycle provide the raw material for cellular synthesis of a wide range of important biomolecules that play important roles in several synthetic pathways.

Amino acid synthesis

TCA cycle intermediates such as α-ketoglutarate and oxaloacetate are precursors for amino acid synthesis. For example, α-ketoglutarate is converted to glutamate, which is a key precursor for the synthesis of other amino acids (e.g., proline, glutamine). Oxaloacetic acid, on the other hand, is a precursor for the synthesis of aspartic acid and other amino acids. These amino acids are critical in protein synthesis, cellular repair, and maintenance of cellular function. Oxaloacetate can be enzymatically reacted to produce aspartic acid, which can be further converted to a variety of important amino acids, such as proline, serine, and cysteine. Through these reactions, the TCA cycle provides cells with a wide range of amino acids that support protein synthesis and other metabolic reactions.

GPT2 catalyzes a reversible reaction between glutamate and pyruvate to produce alanine and α-ketoglutarate, the latter being an intermediate in the TCA cycle. Due to the important role of glutamate in neurotransmission, GPT2 may act as a bridge between synaptic transmission and the TCA cycle. Reduced glutamatergic synaptic transmission in the synaptosomes of GPT2-deficient mice, especially on pyramidal neurons in CA1 hippocampal slices, was manifested as a reduction in excitatory postsynaptic currents (mEPSC). Although mEPSC frequency did not change, inhibitory postsynaptic current (mIPSC) changed. In addition, it was found that glutamate release was reduced in the synaptosomes of GPT2-deficient mice, but was restored to normal levels by supplementation with α-ketoglutarate. Also, a decrease in TCA cycling intermediates and an increase in glutamate dehydrogenase activity were observed in synaptosomes deficient in GPT2, and supplementation with α-ketoglutarate was able to alleviate these metabolic alterations (Baytas O et al., 2024).

Heme Synthesis

Succinyl-coenzyme A (succinyl-CoA) is one of the intermediates of the TCA cycle and serves as an important precursor molecule involved in heme synthesis. Heme is a component of hemoglobin and is responsible for transporting oxygen in the blood. Succinyl coenzyme A is synthesized by reacting with glycine to produce porphyrin, which ultimately synthesizes heme.

Heme synthesis requires the production of succinyl-CoA in the TCA cycle, so the TCA cycle is not only concerned with energy production, but is also involved in the cell's need for oxygen transport and storage, especially in red blood cells. succinyl-CoA is a key intermediate in the synthesis of heme, and although plasma glycine transport proteins can provide glycine, succinyl- CoA must be produced intracellularly by the TCA cycle. For erythropoiesis, however, the TCA cycle must function efficiently in the absence of sepsis support because of the lack of exogenous succinyl-CoA stores. Glutamine plays an important role in heme synthesis, especially through its interaction with KDH(, thus providing a carbon source for ALA synthesis. In addition, glucose supports this process by generating glutamate and glutamine.SUCLA2, as a protein that binds to ALAS2, a key enzyme for ALA synthesis, and FECH, a heme synthesis intermediate synthase, may stabilize the function of these enzymes during the early stages of erythropoiesis. Clathrate is secreted by immune-activated macrophages, which increase succinate levels but exhibit inhibitory effects during heme synthesis. This suggests that during the inflammatory response, clathrate may inhibit heme synthesis by reducing the availability of synthetic precursors, similar to the inhibitory effect of iron-modulators on heme synthesis (Burch JS et al., 2018).

Fatty acid synthesis

Citric acid is an important intermediate in the TCA cycle, which not only participates in a series of reactions in the TCA cycle, but is also able to enter the cytoplasm and participate in fatty acid synthesis through a transporter mechanism. Citric acid is converted in the cytoplasm to acetyl coenzyme A, which is the starting material for fatty acid synthesis.

In senescent endothelial cells, fatty acid metabolic processes are inhibited, particularly fatty acid uptake, acylation processes, and transport to mitochondria. These changes may lead to defective fatty acid oxidation (FAO), which accelerates endothelial senescence.CPT1A is a key enzyme for fatty acid entry into mitochondria, and overexpression of CPT1A promotes fatty acid metabolism, whereas inhibition or knockdown of CPT1A accelerates endothelial senescence. In addition, fatty acid metabolite acetyl coenzyme A is also closely related to endothelial senescence, and overexpression of CPT1A or supplementation of SCFA (short-chain fatty acids) can increase the level of acetyl coenzyme A and regulate endothelial senescence by altering acetylation modifications. Fatty acid metabolism is involved in acetylation modification by generating acetyl coenzyme A, which affects endothelial cell function (Lin T et al., 2022).

Diseases

The TCA cycle (citric acid cycle) is one of the central aspects of cellular energy metabolism, which is not only involved in cellular energy production, but is also closely related to the onset and development of many diseases.

• Poxvirus infection can increase the level of TCA cycle intermediates, especially citrate. Poxvirus regulates cell signaling pathway through its viral factor VGF, especially through EGFR/MAPK/STAT3 signal axis, which stimulates the level of citrate and other TCA cycle intermediates to increase, thus supporting virus replication. VGF plays an important role in the early stage of poxvirus infection, which stimulates TCA cycle through non-classical STAT3 signaling pathway, and the deletion of VGF will reduce the replication of virus in proliferating cells. In addition, the study also found that although the classical STAT3 signaling pathway did not directly participate in the increase of citrate level, the non-classical STAT3 signaling (through phosphorylation at S727 site) played a key role in this process. VGF encoded by VACV is a molecule homologous to epidermal growth factor (EGF), which plays a key role during viral infection. VGF further promotes the increase of TCA cycle intermediates by activating STAT3 signaling pathway. The nonclassical activation of STAT3 (at serine727) depends on the expression of VGF and the signaling pathways of EGFR (epidermal growth factor receptor) and MAPK (mitogen-activated protein kinase) induced by VGF (Pant A et al., 2021).
• In RCC metastatic tissues, the expression of TCA cyclase was significantly absent. The deletion of TCA cyclase expression was more pronounced in RCC than in other types of tumors.The deletion of TCA cyclase expression correlated with reduced expression of the transcription factor PGC-1α.PGC-1α was also lost in RCC tissues. Further studies showed that re-expression of PGC-1α in RCC cells restored TCA cycle enzyme expression and promoted glucose carbon doping into TCA cycle intermediates. It was found that the TGF-β signaling pathway together with histone deacetylase 7 (HDAC7) inhibited the expression of TCA cycle enzymes. Pharmacological inhibition of TGF-β restored TCA cycle enzyme expression and inhibited tumor growth in an in situ model of RCC.HDAC7 affects TCA cycle enzyme expression by inhibiting the expression of genes involved in mitochondrial metabolism through interactions with SMAD proteins. Inhibition of the TGF-β signaling pathway may lead to an increase in TCA cyclase expression in renal cancer, reversing the mitochondrial aspect of the Warburg effect (Nam H et al., 2021).
• Studies have shown that homologous recombination (HR) and metabolic reprogramming are critical for cellular homeostasis, although their relationship in lung adenocarcinoma (LUAD) has rarely been explored. Cell cycle analysis, EdU and cell invasion assays were used in the study to assess the role of SHFM1 in LUAD cell cycle, proliferation and invasion. Levels of isocitrate dehydrogenase (IDH) and α-ketoglutarate dehydrogenase (α-KGDH) were determined by ELISA in A549 cells, and cellular metabolites, particularly the metabolic profile of the TCA cycle, were also analyzed by HPIC-MS/MS. High HR activity was found to be associated with a poor prognosis in LUAD.HR is recognized as an independent prognostic factor in TCGA-LUAD patients. LUAD samples with high HR activity exhibited low immune infiltration, higher genomic instability, and a better response to immune checkpoint inhibitor therapy, as well as higher sensitivity to drugs. Through si-SHFM1 intervention, it was found that the proportion of cells in the G0/G1 phase was significantly increased, the level of DNA replication was reduced, and cell migration and TCA enzyme levels were significantly decreased. This suggests a strong association of SHFM1 between HR and TCA cycling. It is proposed that TCA cycling can promote SHFM1-mediated HR activity, which ultimately leads to a poor prognosis and affects the efficacy of immunotherapy (Xu Z et al., 2024).
• Studies have shown that cancer cells, particularly colorectal cancer cells carrying the PIK3CA mutation, rely on glutamine to replenish intermediates in the tricarboxylic acid (TCA) cycle, which in turn supports the growth and metabolic needs of tumors. Following in vivo infusion of [13C5]-labeled glutamine, these labeled glutamine enter the TCA cycle in tumors and serve as substrates for anaerobic metabolism, helping cancer cells to maintain normal function of the TCA cycle. Colorectal cancer cells carrying oncogenic mutations in the PIK3CA subunit are more glutamine-dependent compared to wild-type PIK3CA colorectal cancers.The labeling of most intermediates in the TCA cycle from glutamine is higher in PIK3CA-mutant tumors than in wild-type tumors, suggesting that PIK3CA-mutant tumors have a stronger requirement for glutamine. The study also used in situ mouse colon tumor models derived from human CRC cells or patient-derived xenografts and found that the tumors utilized glutamine to a greater extent than adjacent normal colon tissue to replenish the TCA cycle. Similar results were observed in colon tumors that emerged spontaneously in genetically engineered mice, further supporting the critical role of glutamine in the TCA cycle (Zhao Y et al., 2019).

References

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