Differential Presynaptic ATP Supply for Basal and High-Demand Transmission

Sobieski, Courtney; Fitzpatrick, Michael J.; Mennerick, Steven

doi:10.1523/jneurosci.2712-16.2017

Cited by 64 publications

(71 citation statements)

References 56 publications

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“…Thus, the absence of distal mitochondria may contribute to the lower efficiency of distal neuropeptide release and endocytosis that occurs as part of the SSV cycle (Fig. 2), which is known to be affected by mitochondria under high demand conditions (Rangaraju et al, 2014;Pathak et al, 2015;Sobieski et al, 2017). Together, the results presented here demonstrate deficient accumulation of two types of organelles -DCVs and mitochondria -and attenuated synaptic function at the most distal sites of extensive monoaminergic innervation.…”

Section: Mitochondrial Distribution and Synaptic Neuropeptide Releasementioning

confidence: 63%

“…Interestingly, endocytosis for SSV recycling and 'kiss-and-run' exocytosis for synaptic neuropeptide release both involve dynamin (Holz, 2013;Wong et al, 2015). Furthermore, in part because of dynamin, SSV recycling is a major consumer of ATP, which is provided by mitochondria when transmission is intense (Rangaraju et al, 2014;Pathak et al, 2015;Sobieski et al, 2017). Therefore, it will be of interest to test the hypothesis that the lower abundance of distal mitochondria limits dynamin function to diminish both endocytosis and neuropeptide release.…”

Section: Function Of Distal Type II Boutonsmentioning

confidence: 99%

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Limited distal organelles and synaptic function in extensive monoaminergic innervation

Tao

Bulgari

Deitcher

et al. 2017

Journal of Cell Science

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Organelles such as neuropeptide-containing dense-core vesicles (DCVs) and mitochondria travel down axons to supply synaptic boutons. DCV distribution among en passant boutons in small axonal arbors is mediated by circulation with bidirectional capture. However, it is not known how organelles are distributed in extensive arbors associated with mammalian dopamine neuron vulnerability, and with volume transmission and neuromodulation by monoamines and neuropeptides. Therefore, we studied presynaptic organelle distribution in Drosophila octopamine neurons that innervate ∼20 muscles with ∼1500 boutons. Unlike in smaller arbors, distal boutons in these arbors contain fewer DCVs and mitochondria, although active zones are present. Absence of vesicle circulation is evident by proximal nascent DCV delivery, limited impact of retrograde transport and older distal DCVs. Traffic studies show that DCV axonal transport and synaptic capture are not scaled for extensive innervation, thus limiting distal delivery. Activity-induced synaptic endocytosis and synaptic neuropeptide release are also reduced distally. We propose that limits in organelle transport and synaptic capture compromise distal synapse maintenance and function in extensive axonal arbors, thereby affecting development, plasticity and vulnerability to neurodegenerative disease.

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Section: Mitochondrial Distribution and Synaptic Neuropeptide Releasementioning

confidence: 63%

Section: Function Of Distal Type II Boutonsmentioning

confidence: 99%

Limited distal organelles and synaptic function in extensive monoaminergic innervation

Tao

Bulgari

Deitcher

et al. 2017

Journal of Cell Science

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“…These studies demonstrate that both glycolysis and oxphos contribute to presynaptic function by generating ATP in an activity‐dependent manner. Similarly, Sobieski et al found that simultaneous inhibition of both glycolysis and oxphos is required to achieve complete inhibition of evoked synaptic transmission (Sobieski, Fitzpatrick, & Mennerick, ). Therefore, it is likely that both oxphos and aerobic glycolysis contribute to synaptic energy metabolism and offer redundancies that confer energetic flexibility for synaptic activity.…”

Section: Axonal Atp Production and Maintenancementioning

confidence: 95%

“…These studies demonstrate that both glycolysis and oxphos contribute to presynaptic function by generating ATP in an activity-dependent manner. Similarly, Sobieski et al found that simultaneous inhibition of both glycolysis and oxphos is required to achieve complete inhibition of evoked synaptic transmission (Sobieski, Fitzpatrick, & Mennerick, 2017).…”

Section: Presynaptic Atp Production In Maintaining Synaptic Transmimentioning

confidence: 96%

“…Considering the heterogenous findings between intracellular compartments and resting versus stimulated nerve cells, it seems imperative to interpret results only within the context measured. For example, in axonal terminals, where presynapses are located, synaptic activity imposes large energetic demands that are met by local ATP synthesis via glycolysis and oxidative phosphorylation (Ashrafi & Ryan, ; Ivannikov et al, ; Rangaraju et al, ; Sheng, ; Sobieski et al, ; Sun et al, ; Verstreken et al, ). To date, the relative contribution of oxphos versus glycolysis within the axonal compartment has not been reported.…”

Section: Energetic Coupling Of Glia and Axonsmentioning

confidence: 99%

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Mechanisms for the maintenance and regulation of axonal energy supply

Chamberlain

Sheng

2019

J of Neuroscience Research

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The unique polarization and high‐energy demand of neurons necessitates specialized mechanisms to maintain energy homeostasis throughout the cell, particularly in the distal axon. Mitochondria play a key role in meeting axonal energy demand by generating adenosine triphosphate through oxidative phosphorylation. Recent evidence demonstrates how axonal mitochondrial trafficking and anchoring are coordinated to sense and respond to altered energy requirements. If and when these mechanisms are impacted in pathological conditions, such as injury and neurodegenerative disease, is an emerging research frontier. Recent evidence also suggests that axonal energy demand may be supplemented by local glial cells, including astrocytes and oligodendrocytes. In this review, we provide an updated discussion of how oxidative phosphorylation, aerobic glycolysis, and oligodendrocyte‐derived metabolic support contribute to the maintenance of axonal energy homeostasis.

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Mitochondria in Neuronal Health: From Energy Metabolism to Parkinson's Disease

et al. 2021

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dendrites, as well as the synthesis of proteins upon stimulation, add to the neuronal energy usage. In this review, we discuss how this enormous amount of ATP is supplied by the different routes of ATP generation and is altered in disease states.Energy metabolism is mediated by the interplay of cytosolic glycolysis with mitochondrial oxidative phosphorylation (OXPHOS). Glucose is the main energy source for the brain and is first imported into the cytoplasm of neurons or astrocytes and converted to pyruvate via glycolysis. Pyruvate is then transported across the mitochondrial membranes and decarboxylated to form acetyl-CoenzymeA (acetyl-CoA). Acetyl-CoA is also the final product of fatty acid β-oxidation, which can occur in mitochondria or peroxisomes alike. Another source of acetyl-CoA is ketone bodies derived from fatty acid oxidation in the liver and secreted into the bloodstream for uptake by extrahepatic tissues. Acetyl-CoA from various sources can then enter the tricarboxylic acid (TCA) cycle to produce the reducing equivalents NADH and FADH, which will finally be fed into the respiratory chain to produce ATP.Although mitochondria are essential for OXPHOS, they are more than just the "powerhouse of the cell," as they also regulate several catabolic processes, such as amino acid or steroid synthesis, influence Ca 2+ and redox equivalent concentrations in the cytosol, and are crucial hubs in the execution of cell death (Figure 1). Thus, it is impossible to review mitochondrial energy metabolism in health and disease without discussing other mitochondrial functions. Therefore, we will briefly describe our current knowledge of mitochondrial function in other catabolic and homeostatic processes. Further, we discuss the cellular responses to mitochondrial dysfunction and how these pathways enhance or deteriorate the pathogenesis of Parkinson's (PD), a neurodegenerative disease that is deeply linked to mitochondrial dysfunction. ATP Sources in NeuronsUnlike most metabolically demanding tissues such as muscle, neurons do not have significant energy stores in the form of glycogen, lipids, or creatine phosphate. [4] As a result, neuronal energy metabolism is tightly regulated, and even acute interruptions in fuel supply rapidly suppress cognitive function. Below, we discuss some of the important sources of ATP in neurons and their contribution to energetic homeostasis and neuronal survival. Mitochondria are the main suppliers of neuronal adenosine triphosphate and play a critical role in brain energy metabolism. Mitochondria also serve as Ca 2+ sinks and anabolic factories and are therefore essential for neuronal function and survival. Dysregulation of neuronal bioenergetics is increasingly implicated in neurodegenerative disorders, particularly Parkinson's disease. This review describes the role of mitochondria in energy metabolism under resting conditions and during synaptic transmission, and presents evidence for the contribution of neuronal mitochondrial dysfunction to Parkinson's disease.

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Differential Presynaptic ATP Supply for Basal and High-Demand Transmission

Cited by 64 publications

References 56 publications

Limited distal organelles and synaptic function in extensive monoaminergic innervation

Limited distal organelles and synaptic function in extensive monoaminergic innervation

Mechanisms for the maintenance and regulation of axonal energy supply

Mitochondria in Neuronal Health: From Energy Metabolism to Parkinson's Disease

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