Succinate Regulates Endothelial Mitochondrial Function and Barrier Integrity

By SWA

Endothelial dysfunction is a hallmark of several pathological conditions, including cancer, cardiovascular disease, and inflammatory disorders.  

The endothelium is a monolayer of cells lining blood vessels that forms a barrier between the blood and surrounding tissues. 

The endothelium, which forms the inner lining of blood vessels, plays a critical role in maintaining vascular homeostasis by regulating barrier integrity, vascular tone, and immune responses. 

Dysregulation of these processes contributes to disease progression. Recent evidence highlights the role of succinate, a key metabolic intermediate, in regulating endothelial mitochondrial function and barrier integrity. In conditions such as inflammation, cancer, and ischemia-reperfusion injury, aberrant succinate metabolism has been implicated in endothelial dysfunction, revealing its dual role as both a metabolite and signaling molecule.

Succinate and its Role in Cellular Metabolism

What is Succinate?

Succinate is a compound central to energy production and signaling within the cell. Chemically, succinate is a dicarboxylic acid with the formula C4H6O4, consisting of a four-carbon chain with two carboxyl (-COOH) groups. Succinate primarily functions as an intermediate in the tricarboxylic acid (TCA) cycle, also known as the Krebs cycle, a series of enzymatic reactions occurring in mitochondria to generate energy in the form of ATP.

Role in Biochemistry

1. Intermediate in the Citric Acid Cycle:

  • Succinate is formed during the conversion of succinyl-CoA to succinate, a reaction catalyzed by the enzyme succinyl-CoA synthetase, which generates one molecule of ATP or GTP.
  • It is subsequently oxidized to fumarate by the enzyme succinate dehydrogenase (SDH). During this reaction, electrons are transferred to FAD (flavin adenine dinucleotide), forming FADH2. FADH2 later donates these electrons to the electron transport chain, aiding in ATP production.

2. Electron Transport Chain (ETC):

  • Succinate dehydrogenase, which oxidizes succinate to fumarate, is a critical component of both the TCA cycle and the ETC. Embedded in the mitochondrial inner membrane, this enzyme passes electrons from FADH2 to ubiquinone (coenzyme Q). The movement of electrons helps establish the proton gradient necessary for oxidative phosphorylation, driving ATP synthesis.

3. Signaling Molecule:

  • Beyond its metabolic functions, succinate serves as a signaling molecule. It binds to and activates succinate receptor 1 (GPR91), a G-protein-coupled receptor involved in processes such as inflammation, angiogenesis, and blood pressure regulation. This signaling role links succinate accumulation to systemic effects in disease.

4. Clinical Significance:

  • Elevated levels of succinate are often observed in pathological conditions such as cancer, hypoxia, and metabolic disorders. Excess succinate can inhibit prolyl hydroxylase (PHD) enzymes, leading to the stabilization of hypoxia-inducible factor-1α (HIF-1α), which is associated with angiogenesis, immune evasion, and cellular survival under hypoxic conditions.

Succinate's Role in Endothelial Function

1. Regulation of Mitochondrial Function in Endothelial Cells

Mitochondria play an essential role in endothelial cells by supplying energy, regulating redox balance, and producing signaling molecules. Succinate directly impacts mitochondrial function through its involvement in the TCA cycle and the ETC. Accumulation of succinate in endothelial cells, particularly under stress conditions, can have dual effects:

  • Energetic Support: Under normal conditions, succinate oxidation via succinate dehydrogenase contributes to ATP production, supporting endothelial cell function and vascular tone regulation.
  • Oxidative Stress and Mitochondrial Dysfunction: Excess succinate accumulation can drive reactive oxygen species (ROS) production through reverse electron transport at complex I of the ETC. Elevated ROS levels disrupt mitochondrial homeostasis and impair endothelial function.

2. Barrier Integrity

Endothelial barrier integrity is essential for maintaining vascular permeability and preventing the leakage of fluids and solutes into surrounding tissues. Succinate influences barrier function through multiple mechanisms:

  • Inflammatory Signaling: Accumulated succinate, acting via the succinate receptor GPR91, can promote the release of pro-inflammatory cytokines, leading to endothelial activation and increased vascular permeability. This is particularly relevant in inflammatory diseases and ischemia-reperfusion injury.
  • ROS-Induced Barrier Disruption: Succinate-induced ROS production damages tight junctions between endothelial cells, further compromising the vascular barrier.

Succinate in Pathological Conditions

Cancer

In cancer, dysregulated cellular metabolism leads to the accumulation of succinate, which stabilizes HIF-1α and promotes angiogenesis to support tumor growth. In the tumor microenvironment, endothelial cells exposed to elevated succinate levels exhibit impaired barrier function, facilitating tumor metastasis.

Cardiovascular Disease

In conditions such as hypertension and atherosclerosis, elevated succinate levels contribute to endothelial dysfunction through ROS production and inflammatory signaling. This exacerbates vascular damage and increases the risk of cardiovascular events.

Inflammatory Disorders

In diseases like sepsis or autoimmune conditions, succinate acts as a pro-inflammatory mediator. By activating GPR91, succinate promotes cytokine release and endothelial activation, leading to impaired barrier integrity and systemic inflammation.

Therapeutic Implications

Targeting succinate metabolism or signaling offers promising therapeutic avenues for conditions associated with endothelial dysfunction:

  1. Inhibitors of Succinate Dehydrogenase (SDH): Modulating SDH activity can reduce ROS production and limit oxidative stress.
  2. GPR91 Antagonists: Blocking succinate receptor signaling could mitigate inflammation and vascular permeability, improving outcomes in inflammatory and cardiovascular diseases.
  3. Antioxidants: Therapies that reduce ROS production or scavenge ROS may restore endothelial mitochondrial function and barrier integrity.

Conclusion

Succinate is more than a simple intermediate of the TCA cycle—it is a key regulator of endothelial mitochondrial function and barrier integrity. While succinate plays an essential role in normal cellular metabolism, its accumulation under pathological conditions contributes to endothelial dysfunction, promoting inflammation, oxidative stress, and vascular permeability. Understanding the dual role of succinate as a metabolic and signaling molecule provides new insights into its involvement in diseases such as cancer, cardiovascular disorders, and inflammation. Targeting succinate metabolism and signaling pathways holds potential for therapeutic interventions aimed at restoring endothelial health and vascular integrity.

Succinate Regulates Endothelial Mitochondrial Function and Barrier Integrity https://www.mdpi.com/2076-3921/13/12/1579

© 2000-2025 Sieglinde W. Alexander. All writings by Sieglinde W. Alexander have a fife year copy right.
Library of Congress Card Number: LCN 00-192742
ISBN: 0-9703195-0-9

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