Biology subjects

Myeong, J.

Publications and source records attributed to Myeong, J..

3 recordsLinked to original sources

bioRxiv2024

Mitochondrial pyruvate transport regulates presynaptic metabolism and neurotransmission

Glucose has long been considered the primary fuel source for the brain. However, glucose levels fluctuate in the brain during sleep, intense circuit activity, or dietary restrictions, posing significant metabolic stress. Here, we demonstrate that the mammalian brain utilizes pyruvate as a fuel source, and pyruvate can support neuronal viability in the absence of glucose. Nerve terminals are sites of metabolic vulnerability within a neuron 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. Importantly, our data reveal that the mitochondrial pyruvate carrier regulates distinct steps in synaptic transmission, 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 synaptic transmission in hippocampal terminals. HIGHLIGHTSO_LISerum pyruvate is taken up by the brain and efficiently oxidized in the TCA cycle. C_LIO_LIThe mitochondrial pyruvate carrier (MPC) is essential for presynaptic energy metabolism. C_LIO_LIAcetylation of the MPC complex modulates mitochondrial pyruvate uptake. C_LIO_LIMPC activity regulates the release and retrieval of synaptic vesicles in nerve terminals. C_LI

neuroscience↗

bioRxiv2023

Metabolic Regulation of Single Synaptic Vesicle Exo- and Endocytosis in Hippocampal Synapses

Glucose has long been considered a primary source of energy for synaptic function. However, it remains unclear under what conditions alternative fuels, such as lactate/pyruvate, contribute to powering synaptic transmission. By detecting individual release events in cultured hippocampal synapses, we found that mitochondrial ATP production from oxidation of lactate/pyruvate regulates basal vesicle release probability and release location within the active zone (AZ) evoked by single action potentials (APs). Mitochondrial inhibition shifted vesicle release closer to the AZ center, suggesting that the energetic barrier for vesicle release is lower in the AZ center that the periphery. Mitochondrial inhibition also altered the efficiency of single AP evoked vesicle retrieval by increasing occurrence of ultrafast endocytosis, while inhibition of glycolysis had no effect. Mitochondria are sparsely distributed along hippocampal axons and we found that nerve terminals containing mitochondria displayed enhanced vesicle release and reuptake during high-frequency trains, irrespective of whether neurons were supplied with glucose or lactate. Thus, synaptic terminals can entirely bypass glycolysis to robustly maintain the vesicle cycle using oxidative fuels in the absence of glucose. These observations further suggest that mitochondrial metabolic function not only regulates several fundamental features of synaptic transmission but may also contribute to modulation of short-term synaptic plasticity. HighlightsO_LISynapses can sustain neurotransmission across various activity levels by bypassing glycolysis and utilizing oxidative fuels. C_LIO_LIMitochondria, but not glycolysis, regulate release probability and nanoscale organization of vesicle release within the active zone. C_LIO_LIMitochondrial inhibition increases the occurrence of vesicle retrieval via ultra-fast endocytosis. C_LIO_LIMitochondrial localization in nerve terminals enhances vesicle release and retrieval in the absence of glucose, representing a form of synaptic plasticity. C_LI

neuroscience↗

bioRxiv2022

Two forms of asynchronous release with distinctive spatiotemporal dynamics in central synapses

Asynchronous release is a ubiquitous form of neurotransmitter release that persists for tens to hundreds of milliseconds after an action potential (AP). How asynchronous release is organized and regulated at the synaptic active zone (AZ) remains debatable. Using nanoscale-precision imaging of individual release events in rat hippocampal synapses, we observed two spatially distinct subpopulations of asynchronous events, ~75% of which occurred inside the AZ and with a bias towards the AZ center, while ~25% occurred outside of the functionally defined AZ, i.e., ectopically. The two subpopulations also differed markedly in temporal properties, with ectopic events occurring at significantly longer time intervals from synchronous events. Both forms of asynchronous release did not, to a large extent, utilize the same release sites as synchronous events. Both asynchronous event subpopulations also differ from synchronous events in some aspects of exo-endocytosis coupling. Specifically, for synchronous but not asynchronous events, coupling with the fast calcium-dependent endocytosis had a gradient decreasing from the AZ center towards its periphery. These results identify two distinct subpopulations of asynchronous release events with distinctive spatiotemporal organization and coupling to endocytic mechanisms.

neuroscience↗