Tracing the lactate shuttle to the mitochondrial reticulum

Area of Science:

• Metabolic Physiology
• Cellular Biology

Background:

• The Lactate Shuttle hypothesis proposes lactate's role beyond anaerobic metabolism.
• Understanding lactate transport is crucial for comprehending cellular energy dynamics.

Purpose of the Study:

• To demonstrate the existence and continuous operation of the Lactate Shuttle at multiple biological levels.
• To elucidate the mechanisms and significance of lactate exchange in various tissues and conditions.

Main Methods:

• Isotope tracer infusion studies using lactate, glucose, glycerol, and fatty acids.
• Measurement of tissue metabolite concentrations.
• Determination of unidirectional and net metabolite exchanges via arterial-venous (a-v) differences and blood flow measurements across key tissue beds (skeletal muscle, heart, brain).

Main Results:

• Demonstrated whole-body lactate shuttling using isotope tracers.
• Provided evidence for lactate shuttling within organs (Organ-Organ), between cells (Cell-Cell), and intracellularly.
• Showcased continuous operation of lactate shuttles in diverse populations (men/women, resting/exercising, trained/untrained, sea level/high altitude).
• Identified lactate exchange between producer cells (e.g., skeletal muscle) and consumer cells (e.g., brain, heart, liver, kidneys).
• Detailed intracellular lactate exchange between cytosol and mitochondria/peroxisomes, and inter-fiber exchange in muscle, and astrocyte-neuron exchange in the brain.

Conclusions:

• The Lactate Shuttle is a fundamental and continuous process in human physiology.
• Lactate serves as an important fuel-energy substrate exchanged between diverse cell types and tissues.
• Mitochondrial respiration in recipient cells drives lactate shuttling through concentration gradients for oxidative metabolism.