The intercellular transport of lactate is crucial for the astrocyte-to-neuron lactate shuttle (ANLS), a model of brain energetics according to which neurons are fueled by astrocytic lactate. In this study we show that the Drosophila chaski gene encodes a monocarboxylate transporter protein (MCT/SLC16A) which functions as a lactate/pyruvate transporter, as demonstrated by heterologous expression in mammalian cell culture using a genetically encoded FRET nanosensor. chaski expression is prominent in the Drosophila central nervous system and it is particularly enriched in glia over neurons. chaski mutants exhibit defects in a high energy demanding process such as synaptic transmission, as well as in locomotion and survival under nutritional stress. Remarkably, locomotion and survival under nutritional stress defects are restored by chaski expression in glia cells. Our findings are consistent with a major role for intercellular lactate shuttling in the brain metabolism of Drosophila.The function of the nervous system requires a large supply of energy, as exemplified by the fact that in the mammalian brain, 50-60% of total ATP produced in the brain is used to support ion transport 1 ; in flies, retinal photoreceptor cells consume about 10% of the ATP production of the whole animal 2 . Our current view about the field of brain energetics has evolved from a one centered in neurons into a one in which astrocytes and neurons play complementary roles to support the high demand of excitability and synaptic activity. In this view, the metabolic communication between neurons and glia is crucial to sustain brain function, relevating the need to unravel the mechanisms that underly this communication.Within cells, several glucose-derived metabolic intermediates can subsequently be oxidized for energy production (i.e. lactate, pyruvate, glutamate, or acetate) 3 , while ketone bodies are mainly used during development and starvation 4,5 . In mammals, it has been estimated that over 10% of glucose entering the brain is converted to lactate despite normal oxygen levels, a metabolic process known as aerobic glycolysis 6 . Lactate production through aerobic glycolysis is a metabolic feature of astrocytes 7,8 . The high-energy demand as the result of glutamatergic synaptic activity is thought to stimulate aerobic glycolysis in astrocytes 9 producing lactate that is secreted and used by neurons as energy source. This metabolic interaction has been termed the astrocyte-neuron lactate shuttle (ANLS) hypothesis 9,10 . Recent evidence from invertebrates supports that metabolic compartmentalization and coupling of neurons and glial cells is a conserved, fundamental feature of bilaterian nervous systems independent of their size 11 . Moreover, the lack of an apparent detrimental effect of glycolytic enzyme deletion in Drosophila neurons suggests that insects may have evolved an extreme version of ANLS, in which neurons would be fueled by lactate and/or alanine produced by glial cells 11 . In vertebrates, lactate is co-transported with proton...

Hereditary spastic paraplegias (HSPs) are characterized by spasticity and weakness of the lower limbs, resulting from length-dependent axonopathy of the corticospinal tracts. In humans, the HSP-related atlastin genes - catalyze homotypic membrane fusion of endoplasmic reticulum (ER) tubules. How defects in neuronal Atlastin contribute to axonal degeneration has not been explained satisfactorily. Using , we demonstrate that downregulation or overexpression of Atlastin in motor neurons results in decreased crawling speed and contraction frequency in larvae, while adult flies show progressive decline in climbing ability. Broad expression in the nervous system is required to rescue the-null mutant ( ) phenotype. Importantly, both spontaneous release and the reserve pool of synaptic vesicles are affected. Additionally, axonal secretory organelles are abnormally distributed, whereas presynaptic proteins diminish at terminals and accumulate in distal axons, possibly in lysosomes. Our findings suggest that trafficking defects produced by Atlastin dysfunction in motor neurons result in redistribution of presynaptic components and aberrant mobilization of synaptic vesicles, stressing the importance of ER-shaping proteins and the susceptibility of motor neurons to their mutations or depletion.

Lactate/pyruvate transport between glial cells and neurons is thought to play an important role in how brain cells sustain the high‐energy demand that neuronal activity requires. However, the in vivo mechanisms and characteristics that underlie the transport of monocarboxylates are poorly described. Here, we use Drosophila expressing genetically encoded FRET sensors to provide an ex vivo characterization of the transport of monocarboxylates in motor neurons and glial cells from the larval ventral nerve cord. We show that lactate/pyruvate transport in glial cells is coupled to protons and is more efficient than in neurons. Glial cells maintain higher levels of intracellular lactate generating a positive gradient toward neurons. Interestingly, during high neuronal activity, raised lactate in motor neurons is dependent on transfer from glial cells mediated in part by the previously described monocarboxylate transporter Chaski, providing support for in vivo glia‐to‐neuron lactate shuttling during neuronal activity.

The transport of lactate and pyruvate between glial cells and neurons plays an important role in the nervous system metabolic coupling. However, the mechanisms and characteristics that underlie the transport of monocarboxylates (MC-T) in vivo are poorly described. Here we use Drosophila expressing genetically-encoded FRET sensors to provide an ex vivo characterization of the MC-T in motor neurons and glial cells from the ventral nerve cord. We show that lactate/pyruvate transport on glial cells is coupled to protons and is more efficient than in neurons. Glial cells maintain higher levels of intracellular lactate generating a positive gradient towards neurons. Moreover, our results show that under increased activity lactate and pyruvate rise on motor neurons and suggest that this depends on the transfer of lactate from glial cells mediated in part by the previously described MC transporter Chaski, giving support to the in vivo glia to neurons lactate shuttling during activity.

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