Astrocytes and neurons communicate via a monocarboxylic acid shuttle

Area of Science:

• Neuroscience
• Cellular Biology
• Biochemistry

Background:

• The Astrocyte-Neuron Lactate Shuttle (ANLS) hypothesis, proposed in 1994, has faced significant debate.
• Proton-linked monocarboxylate transporters (MCTs) play a crucial role in cellular metabolism and transport.

Purpose of the Study:

• To integrate experimental data on MCTs into the ANLS hypothesis.
• To propose a revised model of astrocyte-neuron communication based on MCT function.
• To explain how monocarboxylic acid exchange influences glucose transfer between astrocytes and neurons.

Main Methods:

• Review and integration of existing experimental data on MCTs and their associated proton donors (PDs).
• Characterization of substrate specificity and directionality of MCT complexes.
• Postulation of specific MCT complexes (MCT4·PGK, MCT1·CAII, MCT2) in astrocytes and neurons.

Main Results:

• MCTs function in protein complexes with proton donors, influencing their activity and directionality.
• Specific MCT complexes are proposed for monocarboxylic acid export (MCT4·PGK) and import (MCT1·CAII) in astrocytes.
• Neuronal MCT2 is suggested to preferentially import pyruvic acid (pyrH).
• A shift in the pyrH/l-lactic acid (l-lacH) ratio favors l-lacH, signaling glucose transfer stabilization.

Conclusions:

• Astrocyte-neuron communication is mediated by the exchange of monocarboxylic acids via specific MCT complexes.
• The revised ANLS hypothesis provides a unifying framework for understanding metabolic coupling between astrocytes and neurons.
• This model highlights the role of monocarboxylic acid transport in regulating glucose provision to neurons.