Mitochondrial pyruvate transport regulates presynaptic metabolism and neurotransmission

10.1126/sciadv.adp7423

Abstract

Glucose has long been considered the primary fuel source for the brain. However, glucose levels fluctuate in the brain during sleep or circuit activity, posing major metabolic stress. Here, we demonstrate that the mammalian brain uses pyruvate as a fuel source, and pyruvate can support neuronal viability in the absence of glucose. Nerve terminals are sites of metabolic vulnerability, and we show that mitochondrial pyruvate uptake is a critical step in oxidative ATP production in hippocampal terminals. We find that the mitochondrial pyruvate carrier is post-translationally modified by lysine acetylation, which, in turn, modulates mitochondrial pyruvate uptake. Our data reveal that the mitochondrial pyruvate carrier regulates distinct steps in neurotransmission, namely, the spatiotemporal pattern of synaptic vesicle release and the efficiency of vesicle retrieval—functions that have profound implications for synaptic plasticity. In summary, we identify pyruvate as a potent neuronal fuel and mitochondrial pyruvate uptake as a critical node for the metabolic control of neurotransmission in hippocampal terminals.

<논문요약>

Pyruvate efficiently oxidized in intact brain and serves as metabolic fuel for neuronal cultures

• In vivo metabolomics and isotope tracing show pyruvate enters brain from circulation

• Pyruvate efficiently broken down by oxidative phosphorylation

• Primary cortical neuron cultures can use pyruvate in absence of glucose

• Pyruvate supply partially sustains neuronal viability without glucose

Mitochondrial pyruvate uptake essential for energy metabolism in nerve terminals

• Mitochondrial Pyruvate Carrier (MPC) complex expressed in presynaptic terminals

• MPC inhibition depletes presynaptic ATP in presence of lactate/pyruvate

• MPC crucial for oxidative pyruvate metabolism in nerve terminals

Mitochondrial pyruvate uptake regulates distinct steps in synaptic vesicle (SV) cycle

• MPC inhibition reduces vesicle release probability

• Shifts release closer to active zone center

• Reduces number of release sites

• Impairs SV retrieval during high-frequency stimulation

Sirtuin 3 modulates mitochondrial pyruvate uptake and acetylation of MPC complex

• Sirtuin 3 (Sirt3) regulates MPC1 acetylation in brain

• Sirt3 depletion impairs mitochondrial pyruvate uptake

• MPC1 acetylation sites mapped to K45 and K46

Acetyl mimetic MPC1 mutant impairs mitochondrial pyruvate uptake and synaptic transmission

• MPC1-QQ (acetyl mimetic) fails to restore pyruvate uptake in MPC1-deficient cells

• MPC1-QQ unable to rescue SV retrieval defects in MPC1 knockdown neurons

Discussion

• Pyruvate is a bona fide fuel source for the brain under physiological conditions

• MPC-dependent pyruvate entry into TCA cycle critical for regulating SV cycle

• Sirt3 modulates MPC acetylation and pyruvate transport function

• Posttranslational acetylation of MPC may serve as molecular rheostat matching ATP synthesis with presynaptic energy demand

• Future studies needed to determine effects of MPC acetylation on synaptic plasticity and cognitive performance