Lactic acid
Lactic acid, also known as 2-hydroxypropanoic acid, is a chiral organic compound with the molecular formula C₃H₆O₃ and a molecular weight of 90.08 g/mol, existing as two enantiomers: L-lactic acid (naturally predominant) and D-lactic acid, often in a racemic DL-form commercially.[1] It appears as a colorless to yellow syrupy liquid or crystalline solid with a melting point of 16.8°C, boiling point of 122°C at 15 mm Hg, density of 1.2 g/cm³, and high solubility in water, ethanol, and glycerol, while exhibiting corrosive properties toward metals and tissues with a pKa of 3.86.[1] In biological systems, lactic acid (commonly referred to as lactate in ionized form) is produced through anaerobic glycolysis in muscle cells and other tissues when oxygen demand exceeds supply, such as during intense exercise, converting pyruvate to lactate via lactate dehydrogenase to regenerate NAD⁺ for continued ATP production.[2] This process yields only 2 ATP per glucose molecule compared to 36 in aerobic respiration, and lactate serves not as mere waste but as a key energy substrate, circulating at about 1 mM in blood and fueling the tricarboxylic acid (TCA) cycle in other tissues like the heart and brain, with a turnover flux roughly twice that of glucose.[2] It also participates in the Cori cycle, where lactate from muscles is transported to the liver for gluconeogenesis back into glucose, highlighting its role in metabolic homeostasis and redox buffering.[2] Naturally occurring in sour milk, fruits, and plants due to bacterial fermentation, lactic acid is generated by lactic acid bacteria in processes like yogurt and sauerkraut production.[1] Industrially, lactic acid is primarily produced via fermentation of carbohydrates such as glucose or lactose using lactic acid bacteria, though synthetic methods like lactonitrile hydrolysis exist; this biotechnological approach yields high-purity L-lactic acid for downstream applications.[1] In the food industry, it functions as a generally recognized as safe (GRAS) acidulant, preservative, flavor enhancer, and pH regulator in products like beverages, baked goods, and cultured dairy, contributing antimicrobial effects and sour taste.[1] Medically, it acts as an alkalinizing agent in intravenous solutions, a topical treatment for dry skin and warts, and a component in drug delivery systems.[1] A major industrial use is as a monomer for poly(lactic acid) (PLA), a biodegradable polyester synthesized via polycondensation or ring-opening polymerization of lactide, widely applied in sustainable packaging, textiles, biomedical implants, and 3D printing due to its renewability and compostability.[3]Chemical Properties
Molecular Structure and Formula
Lactic acid is an organic compound with the molecular formula C₃H₆O₃ and a molar mass of 90.08 g/mol.[1] Its structural formula is CH₃CH(OH)COOH, featuring a carboxyl group (-COOH) attached to a carbon atom that also bears a hydroxyl group (-OH) and a methyl group (-CH₃), making it an α-hydroxy acid where the hydroxyl is positioned on the alpha carbon adjacent to the carboxylic acid.[1] This arrangement distinguishes it from other hydroxy acids, such as β-hydroxy acids like 3-hydroxypropanoic acid, by the proximity of the functional groups that influences its reactivity and biological roles.[4] The IUPAC name for lactic acid is 2-hydroxypropanoic acid, reflecting the propanoic acid backbone with a hydroxy substituent at the 2-position.[1] It is commonly referred to as lactic acid, derived from the Latin word lac meaning milk, due to its discovery in sour milk, and is also known as milk acid or 2-hydroxypropionic acid in some contexts.[1] As a member of the alpha-hydroxy acid family, it shares structural similarities with compounds like glycolic acid (the simplest alpha-hydroxy acid) and mandelic acid, all characterized by the alpha-hydroxy carboxylic acid motif that enables applications in cosmetics and biochemistry.[4] Lactic acid is chiral, existing as two enantiomers due to the tetrahedral stereocenter at the alpha carbon: L-lactic acid, which corresponds to the (S)-configuration, and D-lactic acid, the (R)-configuration.[5] These enantiomers are non-superimposable mirror images, with the L-form being the naturally predominant isomer in biological systems such as human muscle metabolism. The stereochemistry is defined by the Cahn-Ingold-Prelog priority rules, where the (S)-enantiomer has the hydroxyl group oriented in a counterclockwise manner when the lowest-priority hydrogen is directed away from the viewer.[6] The enantiomers exhibit optical activity, with L-lactic acid ((S)-2-hydroxypropanoic acid) being dextrorotatory with a specific rotation [α]_D of +3.82° and D-lactic acid ((R)-2-hydroxypropanoic acid) being levorotatory with [α]_D of -3.82°.[7] This optical rotation arises from their differing interactions with plane-polarized light due to the chiral center, allowing enantiomeric separation via polarimetry.[7] In Fischer projections, lactic acid is depicted with the carbon chain vertical, the carboxyl group at the top, and the alpha carbon in the middle; for L-lactic acid, the hydroxyl group projects to the left, while for D-lactic acid, it projects to the right, adhering to the convention where horizontal bonds come out of the plane and vertical bonds recede.[8] This two-dimensional representation simplifies visualization of the stereochemistry without altering the absolute configuration.[8]Physical Characteristics
Lactic acid appears as a colorless to slightly yellow, viscous, hygroscopic liquid in its pure form, readily absorbing moisture from the air.[9] This hygroscopic nature contributes to its handling requirements in laboratory and industrial settings, where it is often stored under controlled humidity conditions. Commercial lactic acid is typically supplied as an 85–88% aqueous solution or as the racemic DL-form, which remains liquid at room temperature.[1] The pure enantiomers (L- and D-forms) of lactic acid are low-melting crystalline solids with a melting point of 53 °C (327 K).[10] The racemic DL-form has a lower melting point of 16.8–18 °C (290–291 K).[9] It exhibits a density of 1.206 g/cm³ at 20 °C.[9] Upon heating, lactic acid does not boil at atmospheric pressure but decomposes at approximately 253 °C, releasing water and forming lactide or other products. Lactic acid is highly soluble in water, being miscible in all proportions, and is also miscible with alcohols, ethers, and acetone.[9] Its solubility is limited in non-polar solvents such as chloroform and benzene, reflecting its polar hydroxy and carboxylic acid groups.[9] Pure lactic acid possesses a mild acidic odor, often described as nearly odorless, and a characteristic sour taste that underscores its role in food applications for acidity and flavor.[9] As a weak acid, it has a pKa value of 3.86 at 25 °C, indicating partial dissociation in aqueous solution according to the equilibrium: \text{CH}_3\text{CH(OH)COOH} \rightleftharpoons \text{CH}_3\text{CH(OH)COO}^- + \text{H}^+ This property governs its behavior in acidic environments.[9]Chemical Reactivity
Lactic acid, or 2-hydroxypropanoic acid, exhibits characteristic reactivity as an α-hydroxy carboxylic acid, primarily driven by its carboxyl and hydroxyl functional groups. The carboxyl group confers acidity, with a pKa value of 3.86 at 25°C, allowing it to donate a proton and form conjugate base lactate ions in aqueous solutions.[11] This acidity enables the formation of various lactate salts through neutralization reactions with bases; for example, reaction with sodium hydroxide yields sodium lactate, a hygroscopic salt used in food preservation and pharmaceuticals.[1] Similarly, esterification of the carboxyl group with alcohols, catalyzed by acids, produces esters such as ethyl lactate, which serves as a green solvent due to its low toxicity and biodegradability.[12] A prominent reaction is the self-condensation polymerization of lactic acid to form polylactic acid (PLA), a biodegradable polyester. This direct polycondensation involves dehydration between the hydroxyl and carboxyl groups of multiple lactic acid molecules, yielding the polymer and water as a byproduct. The basic mechanism is represented by: n \ce{CH3CH(OH)CO2H} \rightarrow \ce{-[CH(CH3)CO2-]_n} + (n-1) \ce{H2O} Optically pure enantiomers (L- or D-lactic acid) are preferred to minimize racemization during polymerization, which typically requires elevated temperatures (150–200°C) and catalysts to achieve high molecular weights.[13] The adjacent hydroxyl group enhances this reactivity compared to simple carboxylic acids, facilitating intramolecular cyclization to lactide intermediates in indirect polymerization routes, though direct condensation is simpler for low-molecular-weight PLA. Lactic acid participates in redox reactions, where it can be oxidized to pyruvic acid via dehydrogenation of the α-carbon, often using metal catalysts like Pt or Pd under aerobic conditions.[14] Enzymatically, lactate dehydrogenase catalyzes this reversible oxidation in biological systems, though chemical catalysis achieves similar transformations non-enzymatically. Reduction of lactic acid, typically via hydrogenation over copper-based catalysts, converts it to 1,2-propanediol, a valuable diol for antifreeze and polymers, with yields up to 88% reported at 200°C.[12] Dehydration under strong acid conditions can also yield acetaldehyde as a minor product.[15] Regarding stability, lactic acid is relatively stable in neutral aqueous solutions but prone to racemization, interconverting between L- and D-enantiomers under heating (e.g., hydrothermal conditions at 250–350°C) or basic environments via enolization of the α-carbon.[16] At high temperatures (>300°C), it decomposes primarily through dehydration to acrylic acid, alongside acetaldehyde and carbon oxides, especially in catalytic vapor-phase processes.[17] This thermal instability arises from the β-elimination involving the hydroxyl group, distinguishing lactic acid from non-hydroxylated carboxylic acids but aligning it with other α-hydroxy acids like mandelic acid, where the methyl substituent moderates steric effects on reactivity.Historical Development
Discovery and Early Research
Lactic acid was first isolated in 1780 by the Swedish chemist Carl Wilhelm Scheele from sour milk, where he obtained it as an impure brown syrup through distillation and precipitation methods.[18] Scheele's work marked the initial recognition of the compound as a distinct organic acid present in fermented dairy products, though its precise nature remained unclear at the time.[19] In 1808, the Swedish chemist Jöns Jacob Berzelius coined the term "lactic acid" (from the Latin lac, meaning milk) while investigating its presence in fluid extracted from meat, expanding its known occurrence beyond milk to animal tissues.[20] Berzelius's experiments demonstrated that lactic acid forms during muscle exertion, linking it to physiological processes for the first time.[21] By the 1830s, Berzelius had proposed an empirical formula for the acid, C3H6O3, based on combustion analysis, providing an early step toward its chemical characterization.[21] Significant progress in understanding lactic acid's origins came in 1857 with Louis Pasteur's studies on fermentation, where he showed that it arises from the microbial conversion of sugars in milk by specific bacteria, including what would later be identified as Lactobacillus species.[22] Pasteur's key experiments involved isolating fermenting agents and observing that the acid formed anaerobically from lactose without oxygen, challenging earlier chemical theories and establishing a biological basis for its production. These findings highlighted the role of living organisms in transforming sugars to lactic acid, paving the way for microbiology. In the 1870s, German chemist Johannes Wislicenus elucidated the molecular structure and confirmed the existence of stereoisomers for lactic acid through synthesis and optical rotation studies, distinguishing the naturally occurring L-form from its D-enantiomer and inactive racemic mixture.[23] Wislicenus's work on isomeric lactic acids, including paralactic acid, verified the formula CH3CH(OH)COOH and demonstrated that spatial arrangement around the chiral carbon accounted for their differing properties, solidifying the compound's structural identity.[24]Industrial and Scientific Advancements
During World War I, lactic acid production saw early industrial scaling primarily for food preservation applications, as fermentation processes using lactic acid bacteria were employed to extend the shelf life of perishable goods amid wartime shortages. This marked a shift from artisanal methods to more organized industrial efforts, particularly in Europe and the United States, where lactic acid's antimicrobial properties helped preserve dairy and vegetable products without refrigeration.[25] In the 1930s, DuPont chemist Wallace Carothers advanced the synthesis of high-molecular-weight polylactic acid through direct condensation of lactic acid monomers, laying the groundwork for its development as a biodegradable polymer.[26] These efforts built on biologically produced lactic acid from fermentation, which remained the primary method; concurrently, chemical synthesis routes for lactic acid, such as the hydrolysis of lactonitrile (derived from acetaldehyde and hydrogen cyanide), were refined and commercialized in the mid-20th century to provide non-fermentative alternatives.[27] Post-1950, biotechnological innovations focused on genetic engineering of bacteria to enhance lactic acid yields, exemplified by modifications to Escherichia coli in the 1990s that redirected metabolic pathways toward homofermentative production of optically pure D- or L-lactate. Researchers engineered E. coli strains by inactivating competing pathways like pyruvate formate-lyase, achieving titers up to 1.2 M lactate under anaerobic conditions, which improved efficiency for industrial applications.[28] Scientific milestones in the mid-20th century included the 1950s elucidation of D- and L-lactic acid's distinct metabolic roles, with studies identifying stereospecific lactate dehydrogenases in bacteria like Lactobacillus plantarum that catalyze the interconversion and utilization of these enantiomers. This work clarified how D-lactate and L-lactate are differentially metabolized, influencing energy production and optical purity in biological systems. In the 2010s, advancements in directed evolution of enzymes, for which Frances Arnold received the 2018 Nobel Prize in Chemistry, have enhanced stereospecific biocatalysis for producing chiral molecules, with applications in metabolic engineering.[29] Recent developments up to 2025 emphasize sustainable bio-based production, integrating algal fermentation and carbon capture to minimize environmental impact. Patents in the 2020s, such as those for extracting value-added products including lactic acid from algal biomass via circular processing, highlight microalgae like Chlorella vulgaris fermented with lactic acid bacteria to yield bioactives while improving aroma and nutritional profiles. Additionally, enzymatic systems converting CO₂ and ethanol directly to L-lactic acid via multienzyme cascades with inherent cofactor regeneration represent carbon capture integration, achieving conversions up to 80% efficiency in vitro and supporting net-negative emission biomanufacturing.[30][31]Production Methods
Fermentative Processes
Lactic acid is primarily produced through fermentative processes utilizing lactic acid bacteria (LAB) under anaerobic conditions, converting carbohydrates into lactic acid as the main product. Homofermentative LAB, such as Lactobacillus species (e.g., L. delbrueckii and L. acidophilus), convert glucose nearly exclusively to lactic acid via the Embden-Meyerhof-Parnas pathway, achieving theoretical yields of 1 g lactic acid per g glucose, represented by the equation:\ce{C6H12O6 -> 2 CH3CH(OH)COOH}
In contrast, heterofermentative LAB like Leuconostoc species produce lactic acid along with byproducts such as ethanol and CO₂ through the phosphoketolase pathway, resulting in lower lactic acid yields of about 0.5 g/g glucose.[32][33] The industrial fermentation process begins with substrate preparation, where renewable carbohydrates like corn starch or sugarcane are hydrolyzed into fermentable sugars using enzymes or acids to ensure accessibility for microbial metabolism. Inoculation follows with a starter culture of selected LAB (typically 1-5% v/v), introduced into the sterilized medium in fermenters. Anaerobic fermentation occurs at 40-50°C for 2-5 days, with pH maintained at 5.5-6.0 by adding calcium carbonate (CaCO₃) to neutralize the acid and prevent inhibition of bacterial growth.[34][32] Optimization strategies compare batch and continuous fermentation modes to enhance efficiency. Batch processes, common for simplicity, achieve high purity but lower productivity (up to 5 g/L/h), while continuous systems with cell recycling yield up to 95% of theoretical values and productivities exceeding 10 g/L/h by maintaining steady-state conditions and avoiding downtime. Downstream purification involves filtration or centrifugation to remove biomass, followed by acidification with sulfuric acid to liberate lactic acid from calcium lactate, producing gypsum as a byproduct.[34][35] Renewable feedstocks such as dairy whey and agricultural waste are increasingly utilized to reduce costs and promote sustainability. Dairy whey, rich in lactose, supports yields of 14-44 g/L lactic acid with LAB like Lactobacillus plantarum or Pediococcus pentosaceus, often supplemented with nitrogen sources for better growth. Agricultural wastes, including corn stover, wheat straw, and sugarcane bagasse, undergo pretreatment (e.g., steam explosion) to yield 26-114 g/L lactic acid after enzymatic hydrolysis, leveraging lignocellulosic sugars.[35][32] Recent advancements include genetically modified organisms (GMOs) for D-lactic acid production, critical for applications requiring specific stereoisomers. In 2024-2025, CRISPR/Cas9-engineered Lactobacillus plantarum strains enhanced xylose utilization from agricultural hydrolysates, achieving up to 41 g/L D-lactic acid with improved inhibitor tolerance. Similarly, modified Lactobacillus paracasei produced 103 g/L L-lactic acid at 99.3% optical purity from corncob residues.[36] Fermentative processes offer environmental benefits through low energy input relative to chemical synthesis, with life cycle assessments showing 11-15% reduced footprint via heat recovery in low-pH operations using waste feedstocks. However, challenges include wastewater management from anaerobic digestion and cooling, which contribute 40-50% of emissions, necessitating strategies like effluent reuse to mitigate pollution.[37][32]
Synthetic Chemical Routes
The primary synthetic route to lactic acid, historically dominant in industrial production, is the cyanohydrin process starting from acetaldehyde. In this method, acetaldehyde reacts with hydrogen cyanide (HCN) in the presence of a base catalyst to form lactonitrile (CH₃CH(OH)CN), which is then hydrolyzed under acidic conditions to yield racemic lactic acid (CH₃CH(OH)COOH).[38] The addition step occurs at high atmospheric pressures in the liquid phase, typically at temperatures around 20-50°C, producing a mixture that requires distillation for lactonitrile purification.[39] Hydrolysis follows using concentrated sulfuric acid (H₂SO₄) or hydrochloric acid (HCl) at elevated temperatures of 100-150°C under pressure, achieving yields of 80-90% after neutralization and purification via distillation or extraction to remove byproducts like ammonium sulfate.[40][41] Modern refinements of the lactonitrile hydrolysis route emphasize catalyst optimization and waste minimization, maintaining the core two-step mechanism but with improved efficiency for large-scale operations. For instance, the process generates a racemic (DL-) mixture of lactic acid isomers, which is advantageous for applications requiring equal proportions of D- and L-forms, such as certain polymer syntheses, though separation is needed for enantiopure products.[39] Alternative chemical pathways include the catalytic oxidation of propylene glycol (1,2-propanediol), where the secondary hydroxyl group is selectively oxidized to the ketone and further rearranged to lactic acid using metal catalysts like gold-based or bimetallic Ag-Pd supported on frameworks such as UiO-66.[42][43] These reactions typically employ oxygen or air as the oxidant at mild temperatures (50-100°C) and atmospheric pressure, yielding up to 90% selectivity to lactic acid under optimized conditions, with the proximity of redox and acid-base sites on the catalyst enhancing conversion rates.[44] Petrochemical-derived routes, though less common due to higher costs and complexity compared to the acetaldehyde-based process, involve intermediates like ethylene glycol obtained from ethylene hydration. Recent advancements include electrochemical oxidation of ethylene glycol on nickel-based electrocatalysts in alkaline media, achieving selective lactic acid production at potentials around 1.4-1.6 V vs. RHE with faradaic efficiencies exceeding 80%.[45] Similarly, dehydrogenative coupling of ethylene glycol with methanol using manganese catalysts has emerged as a greener variant, operating at 180-220°C to produce lactic acid in 70-85% yields.[46] As of 2025, these methods are gaining traction through bio-integrated approaches that hybridize petrochemical feedstocks with catalytic innovations, driven by demand for sustainable alternatives amid rising energy costs.[47] Synthetic routes offer high-purity racemic lactic acid suitable for isomer-specific applications but are energy-intensive due to high-pressure steps and toxic reagents like HCN, rendering them less sustainable than fermentative processes in terms of environmental impact and cost at scale.[38] Purification challenges, including salt removal and color correction, further increase operational expenses, limiting their market share to about 10% of global production.[40]Biological Functions
Metabolic Pathways
Lactic acid plays a central role in cellular metabolism as the end product of anaerobic glycolysis, where it is formed from pyruvate in a reaction catalyzed by lactate dehydrogenase (LDH). This enzyme facilitates the reversible interconversion:\text{Pyruvate} + \text{NADH} + \text{H}^+ \rightleftharpoons \text{Lactate} + \text{NAD}^+
LDH exists as tetrameric isozymes composed of M (muscle-type, encoded by LDHA) and H (heart-type, encoded by LDHB) subunits, with five isoforms (LDH1–LDH5) determined by their subunit composition; LDH5 (M4) predominates in skeletal muscle to support rapid anaerobic energy production, while LDH1 (H4) is prevalent in aerobic tissues like the heart.[48][49] In anaerobic respiration, the conversion of pyruvate to lactate regenerates NAD⁺ from NADH, allowing glycolysis to continue under oxygen-limited conditions when mitochondrial oxidative phosphorylation is impaired. The net reaction for this process is:
\text{Glucose} + 2 \text{ADP} + 2 \text{P}_\text{i} \rightarrow 2 \text{Lactate} + 2 \text{ATP}
This yields only 2 ATP per glucose molecule, far less than the 30–32 ATP from aerobic metabolism, but proceeds at a much higher rate to meet acute energy demands.[50] In microorganisms, particularly lactic acid bacteria (LAB), lactic acid production occurs through fermentation pathways classified as homofermentative or heterofermentative. Homofermentative LAB, such as certain Lactobacillus species, primarily convert glucose to lactate via the Embden-Meyerhof-Parnas (EMP) pathway, achieving nearly 90% conversion efficiency to lactic acid. In contrast, heterofermentative LAB utilize the phosphoketolase pathway, where the enzyme phosphoketolase cleaves xylulose-5-phosphate into glyceraldehyde-3-phosphate and acetyl-phosphate, yielding equimolar amounts of lactate, ethanol, and CO₂ as end products.[51] Regulation of lactic acid metabolism involves both enzymatic and genetic mechanisms. LDH activity is allosterically modulated by pH and the NADH/NAD⁺ ratio; acidic conditions (pH 5.0–6.5) induce homotropic allosteric transitions in LDH-A, shifting kinetics from hyperbolic to sigmoidal and promoting tetramer dissociation into dimers, which pyruvate can reverse. The NADH/NAD⁺ ratio influences the equilibrium toward lactate formation under reductive conditions. At the genetic level, ldh gene expression, especially LDHA, is upregulated in response to hypoxia via transcription factors like HIF-1α, enhancing glycolytic flux.[52][53] Isomer specificity is critical in lactic acid metabolism, with mammals predominantly producing and utilizing L-lactate through LDHA, which integrates into the lactate shuttle for inter-tissue energy transfer. In contrast, some bacteria, including certain LAB, generate D-lactate via distinct D-LDH enzymes during fermentation.[54]
Role in Muscle Exercise
During high-intensity exercise, skeletal muscle relies increasingly on anaerobic glycolysis for ATP production when oxygen delivery cannot meet demand, leading to the accumulation of lactate. The anaerobic threshold represents the exercise intensity at which lactate production surpasses its clearance rate, resulting in a marked rise in blood lactate levels, typically exceeding 4 mmol/L, often referred to as the onset of blood lactate accumulation (OBLA).[55][56] This buildup occurs as glycolytic flux accelerates, outpacing mitochondrial oxidation, and serves as a marker of the transition to greater anaerobic contribution, influencing endurance performance.[57] Lactate accumulation contributes to muscle fatigue primarily through the associated proton (H⁺) accumulation, which lowers intramuscular pH and induces acidosis, thereby impairing actin-myosin cross-bridge cycling and reducing force production during contraction. Contrary to the long-held myth that lactic acid directly causes the "burn" sensation or fatigue, research has established that the protons arise mainly from ATP hydrolysis and other metabolic processes, not from lactate dissociation itself, which remains largely neutral at physiological pH.[58][59][60] Post-exercise, lactate is cleared from the bloodstream primarily through hepatic gluconeogenesis via the Cori cycle, where it is converted back to glucose for recycling to muscles, facilitated by monocarboxylate transporters MCT1 (for uptake) and MCT4 (for efflux) in skeletal muscle and liver tissues. Endurance training induces adaptations such as increased mitochondrial density and oxidative enzyme activity, which enhance lactate clearance and reduce its accumulation during submaximal efforts by improving aerobic capacity. Recent studies, including those from 2025, further explore lactate's role as a potential signaling molecule that may activate pathways like mTOR and contribute to adaptive remodeling in response to high-intensity training, though findings on muscle hypertrophy are mixed, particularly in human studies.[61][62][63][64] In individuals with mitochondrial diseases, such as mitochondrial myopathies, exercise provokes exaggerated hyperlactatemia due to defective oxidative phosphorylation, which limits aerobic metabolism and forces reliance on glycolysis, resulting in rapid lactate buildup and severe fatigue even at low intensities.[65][66]Functions in Neural Tissues
In the central nervous system, lactic acid, primarily in its L-lactate form, is proposed to play a crucial role in energy metabolism through the astrocyte-neuron lactate shuttle (ANLS) hypothesis, although influential, remains subject to debate in the scientific community.[67] In this proposed mechanism, astrocytes take up glutamate released from active neurons, leading to increased glucose uptake and glycogen breakdown, which results in the production of lactate via glycolysis. This lactate is then exported from astrocytes and taken up by adjacent neurons through monocarboxylate transporters (MCTs), such as MCT1 and MCT2, for subsequent oxidation.[68] Neurons utilize this shuttled lactate as a key energy substrate by converting it to pyruvate in the cytosol via lactate dehydrogenase (LDH), following the reaction:\text{Lactate} + \text{NAD}^+ \rightarrow \text{Pyruvate} + \text{NADH}
This process regenerates NAD⁺ for continued glycolysis in astrocytes while providing pyruvate to fuel neuronal oxidative phosphorylation in mitochondria. Under basal conditions, lactate oxidation accounts for approximately 8-20% of the brain's total energy requirements, with the proportion increasing during heightened neural activity or lactate infusion.[69][70] During hypoxic or ischemic conditions, such as those occurring in stroke or transient oxygen deprivation, brain lactate levels rise significantly as glycolysis shifts toward lactate production to maintain ATP levels when oxidative metabolism is impaired. This elevated lactate serves as an alternative fuel for neurons, supporting energy demands in oxygen-limited environments and potentially mitigating immediate cellular damage. However, in prolonged ischemia, excessive lactate accumulation contributes to acidosis, exacerbating neuronal injury by promoting excitotoxicity, inflammation, and cell death through mechanisms like impaired ion homeostasis.[71][72] Beyond its metabolic role, lactate acts as a signaling molecule in neural tissues via the hydroxycarboxylic acid receptor 1 (HCAR1), a G-protein-coupled receptor expressed on neurons and glia. Activation of HCAR1 by lactate modulates neuronal excitability, reducing synaptic transmission and network activity through presynaptic inhibition and decreased cAMP levels, thereby influencing processes like seizure thresholds. In cognitive functions, HCAR1-mediated lactate signaling enhances memory consolidation and long-term potentiation (LTP) in the hippocampus by promoting serine synthesis and NMDA receptor activation; studies from the early 2020s have shown that lactate infusion restores LTP deficits in aging or disease models, linking it to improved learning and mood regulation via antidepressant-like effects on eEF2 phosphorylation.[73][74][75]