TY - JOUR
T1 - Mitochondrial pyruvate transport regulates presynaptic metabolism and neurotransmission
AU - Tiwari, Anupama
AU - Myeong, Jongyun
AU - Hashemiaghdam, Arsalan
AU - Stunault, Marion I.
AU - Zhang, Hao
AU - Niu, Xiangfeng
AU - Laramie, Marissa A.
AU - Sponagel, Jasmin
AU - Shriver, Leah P.
AU - Patti, Gary J.
AU - Klyachko, Vitaly A.
AU - Ashrafi, Ghazaleh
N1 - Publisher Copyright:
© 2024 The Authors, some rights reserved;
PY - 2024/11/15
Y1 - 2024/11/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85209695396&partnerID=8YFLogxK
U2 - 10.1126/sciadv.adp7423
DO - 10.1126/sciadv.adp7423
M3 - Article
C2 - 39546604
AN - SCOPUS:85209695396
SN - 2375-2548
VL - 10
JO - Science Advances
JF - Science Advances
IS - 46
M1 - eadp7423
ER -