Inhibition of the mitochondrial pyruvate carrier protects from excitotoxic neuronal death

Abstract

In cortical neurons and hippocampal slice cultures, blocking mitochondrial pyruvate uptake rewires metabolism to increase reliance on glutamate to fuel the TCA cycle. This diminishes the readily releasable pool of neuronal glutamate and minimizes the positive-feedback cascade of excitotoxic injury.

Neurons eat glutamate to stay alive

“…Less glutamate release could be protective to excitotoxic stress that is elicited when glutamate activates postsynaptic receptors. Consistent with this model, when Divakaruni et al (2017) simulated neurons in which pyruvate entry in mitochondria was blocked, they observed less cell death than in Neurons are thought to primarily rely on glucose to fuel mitochondrial metabolism. In this issue, Divakaruni et al (2017.…”

“…In nonneuronal cells, both glutamate and glutamine can be readily oxidized to produce energy, but is this not so in neurons? Divakaruni et al (2017) revisited the dogma that neurons depend on glucose to fuel their mitochondrial metabolism by performing 13 C tracer analyses. This methodology allows determining the fate of 13 C-labeled nutrients by following the labeled carbons through the metabolic network.…”

“…Strikingly, they found that, even in glucose-rich conditions, neurons use alternative nutrients for mitochondrial energy production, such as the amino acid leucine and β-hydroxybutyrate. Having established that neurons are able to use alternative nutrients in their mitochondrial metabolism, Divakaruni et al (2017) next asked how neurons respond when inhibiting the entry of pyruvate into the mitochondria, thus largely precluding the use of glucose. Pyruvate is the major downstream product of glucose and is transported into the mitochondria via the mitochondrial pyruvate carrier (MPC).…”

“…Nonetheless, it would also be interesting to test such metabolic flexibility in vivo by infusing 13 C-labeled glutamate to determine its in vivo use and by isolating specific neuronal cell types from an intact brain. Moreover, it would be interesting to investigate what other nutrients beyond the ones discovered by Divakaruni et al (2017) can sustain the mitochondrial metabolism of neurons.Another interesting issue that Divakaruni et al (2017) touch upon is the advantage for neurons to switch specifically to glutamate rather than increase their use of leucine or β-hydroxybutyrate. The latter two substrates were already known as substrates for energy production in neurons, but, unlike pyruvate that refills mitochondrial metabolites via pyruvate carboxylase, the use of leucine or β-hydroxybutyrate only allows sustaining of energy production (Hassel and Brâthe, 2000).…”

“…Nonetheless, it would also be interesting to test such metabolic flexibility in vivo by infusing 13 C-labeled glutamate to determine its in vivo use and by isolating specific neuronal cell types from an intact brain. Moreover, it would be interesting to investigate what other nutrients beyond the ones discovered by Divakaruni et al (2017) can sustain the mitochondrial metabolism of neurons.…”