Lactic acid: Key Roles in Human Metabolism, Diseases, and Health Implications

Explore the multifaceted role of lactic acid in human metabolism, its impact on diseases such as cancer and cardiovascular conditions, and the emerging insights into its therapeutic potential. Gain a comprehensive understanding of lactic acid's functions in energy metabolism, inflammation, and neurological health.

1. Introduction to Lactic Acid

2. Lactic Acid Metabolism: Production and Clearance

3. Lactic Acid in Human Health and Diseases

• Lactic Acid in Energy Metabolism
• Lactic Acid in Cancers
• Lactic Acid in Inflammation
• Lactic Acid in Neurodegenerative Diseases
• Lactic Acid in Cardiovascular Diseases
• Lactic Acid in Sepsis and Septic Shock

Introduction to Lactic Acid

Lactic acid, also known as 2-hydroxypropanoic acid, alpha-hydroxypropionic acid or lactate, is a simple organic compound with the molecular formula C3H6O3. Lactic acid is a crucial player in human metabolism especially in energy production and cellular functioning. The discovery of lactic acid dates back to the late 18th century when Swedish chemist Carl Wilhelm Scheele first isolated it from sour milk in 1780 [1]. However, it was French chemist Joseph Louis Gay-Lussac who identified its chemical structure in 1808, elucidating its composition as a carboxylic acid. 

Structurally, lactic acid consists of a three-carbon chain (propionic acid) with a hydroxyl group (-OH) attached to the second carbon atom. The presence of both a carboxyl group (-COOH) and a hydroxyl group in its structure classifies lactic acid as a hydroxy carboxylic acid. The chemical structure of lactic acid can be represented as CH3-CHOH-COOH, where the middle carbon (the second carbon) is chiral, meaning it has four different substituents. This chiral center gives rise to two enantiomeric forms of lactic acid: L-lactic acid and D-lactic acid. Visually, lactic acid appears as a colorless, water-soluble liquid with a slightly acidic taste. 

Lactic Acid Metabolism: Production and Clearance

Lactic acid metabolism involves the utilization and conversion of lactic acid within the body, encompassing both its production and clearance. Here's a breakdown of the key steps and pathways involved [2,3]:

1. Lactic Acid Production: 

Lactate is a classical byproduct of glucose metabolism, and the main lactate production pathway depends on glycolysis. Glucose is transported into the cell and converted to pyruvate through a series of enzymatic reactions in the glycolysis pathway.

Under anaerobic conditions or in the absence of oxygen, pyruvate is converted to lactic acid by the enzyme lactate dehydrogenase (LDH), using NADH as a cofactor. This reaction regenerates NAD+ necessary for the continuation of glycolysis.

2. Lactic Acid Clearance:

Lactic acid produced in muscles and other tissues is transported via the bloodstream to the liver for clearance. In the liver, lactic acid is converted back to pyruvate by LDH.

Pyruvate generated from lactic acid can enter the mitochondrial matrix and be oxidized to acetyl-CoA by pyruvate dehydrogenase. Acetyl-CoA enters the TCA cycle, where it undergoes a series of oxidation-reduction reactions to produce NADH, FADH2, and ATP.

Pyruvate derived from lactic acid can also serve as a substrate for gluconeogenesis in the liver. In gluconeogenesis, pyruvate is converted to oxaloacetate by pyruvate carboxylase and then to glucose-6-phosphate by phosphoenolpyruvate carboxykinase and other enzymes. Glucose-6-phosphate can be further processed to produce glucose, which is released into the bloodstream for use by other tissues.

Lactic Acid in Human Health and Diseases

Lactic acid, often considered a metabolic waste product, has garnered significant attention for its diverse roles in various diseases, beyond its traditional association with muscle fatigue and acidosis. Here are some important functions of lactic acid in diseases, along with recent findings and underlying mechanisms:

1. Lactic Acid in Energy Metabolism

Lactic acid, primarily produced during anaerobic glycolysis, serves as a critical metabolic intermediate and energy substrate in various tissues. Recent studies have highlighted its role in metabolic flexibility, particularly during periods of high energy demand or oxygen limitation [4]. One key mechanism involves the conversion of pyruvate to lactate by lactate dehydrogenase (LDH) in the cytosol, which regenerates NAD+ and allows glycolysis to continue. Moreover, lactate can be transported between cells and tissues via monocarboxylate transporters (MCTs), facilitating its utilization as an energy source in organs such as skeletal muscle, heart, and brain [5]. Interestingly, lactate has been shown to act as a signaling molecule, regulating gene expression, cellular metabolism, and physiological adaptations to exercise. Furthermore, emerging evidence suggests that lactate contributes to the regulation of systemic metabolic homeostasis and the coordination of energy metabolism across different tissues [6,7].

2. Lactic Acid in Cancers

In cancer metabolism, lactic acid plays a dual role, serving as both a metabolic byproduct and a signaling molecule that promotes tumor growth and progression [8]. Cancer cells exhibit increased aerobic glycolysis, leading to elevated lactate production, even in the presence of oxygen (the Warburg effect) [9]. Lactic acid is exported from cancer cells via MCTs, contributing to extracellular acidification and the remodeling of the tumor microenvironment. This acidic environment promotes tumor invasion, angiogenesis, and immune evasion, facilitating metastasis and therapy resistance [10]. Moreover, recent studies have revealed novel mechanisms by which lactate regulates cancer cell metabolism, epigenetics, and immune responses, highlighting its potential as a therapeutic target in cancer treatment [11].

3.Lactic Acid in Inflammation

Lactic acid has emerged as a central regulator of immune responses and inflammation, exerting context-dependent effects on immune cell function and cytokine production. During inflammation, immune cells such as macrophages and neutrophils produce lactate as a byproduct of glycolysis, contributing to the acidic microenvironment at inflammatory sites [8]. Lactate can modulate immune cell metabolism, polarization, and effector functions, influencing the balance between pro-inflammatory and anti-inflammatory responses [12]. Moreover, recent studies have elucidated novel mechanisms by which lactate regulates immune cell signaling pathways, inflammasome activation, and cytokine production, highlighting its role as a metabolic regulator of inflammation [13].

4.Lactic Acid in Neurodegenerative Diseases

In neurodegenerative diseases such as Alzheimer's and Parkinson's disease, dysregulated lactate metabolism has been implicated in neuronal dysfunction and neurodegeneration. Lactic acid serves as an alternative energy substrate for neurons and glial cells in the brain, supporting neuronal survival and function under metabolic stress [14]. However, excessive lactate production can lead to neuronal damage, oxidative stress, and mitochondrial dysfunction, contributing to the pathogenesis of neurodegenerative diseases [15]. Additionally, recent studies have identified aberrant lactate metabolism as a potential biomarker and therapeutic target for neurodegenerative diseases, highlighting the importance of understanding the mechanisms underlying lactate-mediated neurotoxicity [16].

5.Lactic Acid in Cardiovascular Diseases

Lactic acid accumulation is associated with cardiovascular diseases such as myocardial ischemia, heart failure, and hypertension [17]. During myocardial ischemia, inadequate oxygen supply leads to anaerobic glycolysis and lactate production in cardiac myocytes, contributing to myocardial injury and dysfunction. Elevated lactate levels serve as a biomarker of tissue hypoxia and correlate with disease severity and prognosis in patients with heart failure and other cardiovascular conditions. Mechanistically, lactate-induced acidosis and oxidative stress impair cardiac contractility, induce arrhythmias, and promote myocardial remodeling, highlighting the multifaceted role of lactate in cardiovascular pathophysiology.

6. Lactic Acid in Sepsis and Septic Shock

Lactic acidosis, resulting from tissue hypoxia and mitochondrial dysfunction, is a common feature of sepsis and septic shock [18]. Elevated lactate levels serve as a marker of tissue perfusion and oxygenation status, reflecting the severity of systemic inflammation and organ dysfunction. Lactic acidosis contributes to cardiovascular instability, organ failure, and mortality in septic patients. Mechanistically, lactate-induced acidosis impairs cellular metabolism, microvascular function, and immune responses, exacerbating tissue damage and systemic inflammation. Recent studies have highlighted the potential utility of lactate as a prognostic biomarker and therapeutic target in sepsis management, emphasizing the importance of understanding its role in septic pathophysiology [19].

Reference

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2.Li X, Yang Y, Zhang B, et al. Lactate metabolism in human health and disease. Signal Transduct Target Ther. 2022;7(1):305. Published 2022 Sep 1. doi:10.1038/s41392-022-01151-3

3.Rabinowitz JD, Enerbäck S. Lactate: the ugly duckling of energy metabolism. Nat Metab. 2020;2(7):566-571. doi:10.1038/s42255-020-0243-4

4.Brooks GA. Cell-cell and intracellular lactate shuttles. J Physiol. 2009;587(Pt 23):5591-5600. doi:10.1113/jphysiol.2009.178350

5.Brooks GA. The Science and Translation of Lactate Shuttle Theory. Cell Metab. 2018;27(4):757-785. doi:10.1016/j.cmet.2018.03.008

6.Brooks GA. Lactate as a fulcrum of metabolism. Redox Biol. 2020;35:101454. doi:10.1016/j.redox.2020.101454

7.Daw CC, Ramachandran K, Enslow BT, et al. Lactate Elicits ER-Mitochondrial Mg2+ Dynamics to Integrate Cellular Metabolism. Cell. 2020;183(2):474-489.e17. doi:10.1016/j.cell.2020.08.049

8.Zhou HC, Xin-Yan Yan, Yu WW, et al. Lactic acid in macrophage polarization: The significant role in inflammation and cancer. Int Rev Immunol. 2022;41(1):4-18. doi:10.1080/08830185.2021.1955876

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11.Chen L, Huang L, Gu Y, Cang W, Sun P, Xiang Y. Lactate-Lactylation Hands between Metabolic Reprogramming and Immunosuppression. Int J Mol Sci. 2022;23(19):11943. Published 2022 Oct 8. doi:10.3390/ijms231911943

12.Haas R, Smith J, Rocher-Ros V, et al. Lactate Regulates Metabolic and Pro-inflammatory Circuits in Control of T Cell Migration and Effector Functions. PLoS Biol. 2015;13(7):e1002202. Published 2015 Jul 16. doi:10.1371/journal.pbio.1002202

13.Pucino V, Bombardieri M, Pitzalis C, Mauro C. Lactate at the crossroads of metabolism, inflammation, and autoimmunity. Eur J Immunol. 2017;47(1):14-21. doi:10.1002/eji.201646477 

14.Pellerin L, Magistretti PJ. Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization. Proc Natl Acad Sci U S A. 1994;91(22):10625-10629. doi:10.1073/pnas.91.22.10625

15.Magistretti PJ, Allaman I. Lactate in the brain: from metabolic end-product to signalling molecule. Nat Rev Neurosci. 2018;19(4):235–249. doi:https://doi.org/10.1038/nrn.2018.19. 

16.Sun Y, Wang Y, Chen ST, et al. Modulation of the Astrocyte-Neuron Lactate Shuttle System contributes to Neuroprotective action of Fibroblast Growth Factor 21. Theranostics. 2020;10(18):8430-8445. Published 2020 Jul 9. doi:10.7150/thno.44370

17.Ouyang J, Wang H, Huang J. The role of lactate in cardiovascular diseases. Cell Commun Signal. 2023;21(1):317. Published 2023 Nov 3. doi:10.1186/s12964-023-01350-7

18.Nolt B, Tu F, Wang X, et al. Lactate and Immunosuppression in Sepsis. Shock. 2018; 49 (2):120-125. doi:10.1097/SHK.0000000000000958

19.Kanashvili B, Saganelidze K, Ratiani L. The role of procalcitonin and blood lactic acid values in prognosis of sepsis and septic shock in polytrauma patients. Georgian Med News. 2018; (279):102-107.

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