Lactate Metabolism

Lactate is the conjugate base of lactic acid (an organic 3-C acid)

Production:

• It is produced by anaerobic metabolism of pyruvate either:
  • Physiologically → in RBC (no mitochondria), renal medulla (↓ PO2), cornea/ lens (↓ PO2) → hence, normal plasma [lactate] is 0.5-2 mmol/L (and NOT zero!)
  • Pathologically → reduced tissue perfusion and/or O2 delivery (Eg. shock, hypoxaemia) → thus, plasma [lactate] ↑↑↑ (> 2 mmol/L)
• Plasma [lactate] is 0.5 – 2 mM (and NOT zero) due to physiological production → it can be measured clinically as an indicator of anaerobic metabolism (Ie. ↑ anaerobic metabolism due to pathological situations lead to ↑ [lactate])

Fate of lactate:

• Persistent anaerobic metabolism (Ie. ongoing hypoxia) causes an accumulation of cellular lactate → this diffuses out of the cell into plasma along its [ ] gradient → lactate can then be:
  • Used as a fuel source by the heart and brain
  • Transported to the liver where it is:
    • Converted back to glucose via gluconeogenesis (requires 6x ATP), which is then transported back peripherally for use → “Cori cycle”
    • Converted to pyruvate intermediate → utilised locally in TCA cycle for ATP production via oxidative phosphorylation
• Resolution of hypoxia (Ie. tissue O2 tension restored) → intracellular lactate can be oxidised back to pyruvate for use in local tissue aerobic metabolism (Ie. fed into TCA cycle)

Functions of Lactate:

Lactate Sink:

• Lactate acts as a sink in heart, liver, muscle etc, allowing a period of ongoing ATP production from glycolysis when:
  • cells become oxygen deplete
  • Kreb’s cycle is inhibited
  • Other causes of pyruvate accumulation: circulating catecholamines, exercise, sepsis or lack of mitochondria (RBCs)

Lactate Shuttle:

• Intracellular shuttle:
  • Lactate may be shuttle out of:
    • mitochoncrial membrane
    • peroxisomes
  • into cytoplasm of myocytes, neurons, astrocytes
  • Ixydised by cytoplasmic LDH to pyruvate, generating NADH for energy use
• Intercellular shuttle:
  • Excess lactate, formed within fast-twitch fibres, is transported to other cells within the body with the oxidative capability to metabolize lactate, such as type I (slow-twitch) muscle cells, enhancing their excitability and limiting fatigue
  • Furthermore, once in circulation, lactate attaches to red blood cells (RBCs) and is disassociated in the liver where inter-conversion via gluconeogenesis facilitates glucose formation, providing an alternative aerobic energy source.

Lactate as a signaling molecule:

• Redox signaling by intracellular shuttles
• Gene expression
  • Increased intracellular levels of lactate can act as a signalling hormone, inducing changes in gene expression that will upregulate genes involved in lactate removal, and stimulates mitochondrial biogenesis.
• Control of lipolysis
  • the shuttle regulates FFA mobilization by controlling plasma lactate levels.
  • lactate functions to inhibit lipolysis in fat cells through activation of an orphan G-protein couple receptor (GPR81) that acts as a lactate sensor, inhibiting lipolysis in response to lactate

Bianca / JC 2021

Answer by Bianca, JC