ERC Starting Grant - SynaptoEnergy

The human brain, despite constituting just 2.5% of total body weight, is extremely energy demanding and consumes nearly 20% of the body’s basal metabolic rate. Within the brain, synapses are considered to be the primary locus of energy consumption and impaired metabolic states, such as ischemic attacks or severe hypoglycemia, strongly limit fuel availability at synapses, threatening synaptic transmission and causing severe cognitive dysfunction. The brain uses glucose and oxygen as main fuels, converting them into usable chemical energy in the form of ATP through the coordinated function of glycolysis and mitochondrial oxidative phosphorylation (OxPhos). However, while there is extensive literature describing the biochemical reactions that generate ATP in these pathways, very little is known about their actual molecular implementation in neurons for sustaining synaptic function and the molecular link between cognitive dysfunction and impaired metabolic states is yet poorly understood.

Our team is studying, funded by an ERC Starting Grant, how synapses activate on demand OxPhos and glycolysis by combining cutting-edge optophysiology tools that we and others have developed, together with innovative proteomic and functional screenings, coupling these powerful tools with precise genetic and metabolic neuronal manipulations in primary neurons and intact brain tissue.

Using state of the art technologies, we have discovered that a particular protein called LETM1 is essential to regulate the ability of neurons to produce energy when it is needed. When this protein is removed from neurons, this results in increased ATP levels at the synapse. We are currently investigating this exciting direction, which will help us to better understand the molecular link between bioenergetics and brain dysfunction.