The Role of Mitochondrially Derived ATP in Synaptic Vesicle Recycling

Pathak, Divya; Shields, Lauren; Mendelsohn, Bryce A.; Haddad, Dominik; Lin, Wei‐Ting; Gerencser, Akos A.; Kim, Hwajin; Brand, Martin D.; Edwards, Robert H.; Nakamura, Ken

doi:10.1074/jbc.m115.656405

Cited by 233 publications

(239 citation statements)

References 62 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 Releasesupporting

confidence: 48%

“…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 Releasesupporting

confidence: 48%

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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“…Mitochondrial ATP provision was also recently proposed to contribute to the variability of presynaptic strength 33, particularly during long stimulation trains. However, other studies using presynaptically targeted ATP probes showed that even long stimulation periods of 60 s do not necessarily lead to a depletion of presynaptic ATP, because activity‐driven ATP generation (through glycolysis and oxidative phosphorylation) 38 and ATP diffusion 39 can serve to maintain presynaptic ATP levels. Thus, the importance of local mitochondrial ATP provision at terminals occupied by a mitochondrion in sustaining vesicular release may vary dependent on signalling demands (e.g.…”

Section: Resultsmentioning

confidence: 97%

Miro1‐dependent mitochondrial positioning drives the rescaling of presynaptic Ca ²⁺ signals during homeostatic plasticity

et al. 2016

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Mitochondrial trafficking is influenced by neuronal activity, but it remains unclear how mitochondrial positioning influences neuronal transmission and plasticity. Here, we use live cell imaging with the genetically encoded presynaptically targeted Ca2+ indicator, SyGCaMP5, to address whether presynaptic Ca2+ responses are altered by mitochondria in synaptic terminals. We find that presynaptic Ca2+ signals, as well as neurotransmitter release, are significantly decreased in terminals containing mitochondria. Moreover, the localisation of mitochondria at presynaptic sites can be altered during long‐term activity changes, dependent on the Ca2+‐sensing function of the mitochondrial trafficking protein, Miro1. In addition, we find that Miro1‐mediated activity‐dependent synaptic repositioning of mitochondria allows neurons to homeostatically alter the strength of presynaptic Ca2+ signals in response to prolonged changes in neuronal activity. Our results support a model in which mitochondria are recruited to presynaptic terminals during periods of raised neuronal activity and are involved in rescaling synaptic signals during homeostatic plasticity.

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“…Postnatal hippocampal neurons were cultured from P0 rat pups as described (Pathak et al, 2015). Expression of PINK1-V5 and its localization to mitochondria were tested by infecting neurons at DIV4 with AAV-PINK1-V5 (WT or G309D).…”

Section: Methodsmentioning

confidence: 99%

“…Expression of PINK1-V5 and its localization to mitochondria were tested by infecting neurons at DIV4 with AAV-PINK1-V5 (WT or G309D). At DIV7, neurons were treated overnight with 10 µM carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone (FCCP; Sigma), fixed with 4% paraformaldehyde in phosphate-buffered saline (PBS), and immunostained and imaged for the mitochondrial marker Tom20 (rabbit, Santa Cruz Biotechnology, SC-11415, 1:1000) and the V5 epitope (mouse, Life Technologies, R960-25, 1:1000) as described (Pathak et al, 2015). Expression of full-length PINK1-WT/G309D-V5 in cell lysates was determined by infecting neurons at DIV5 with PINK1-WT-V5 or PINK1-G309D-V5 viruses.…”

Section: Methodsmentioning

confidence: 99%

Long-term oral kinetin does not protect against α-synuclein-induced neurodegeneration in rodent models of Parkinson's disease

Orr

Rutaganira

Roulet

et al. 2017

Neurochemistry International

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Mutations in the mitochondrial kinase PTEN-induced putative kinase 1 (PINK1) cause Parkinson's disease (PD), likely by disrupting PINK1's kinase activity. Although the mechanism(s) underlying how this loss of activity causes degeneration remains unclear, increasing PINK1 activity may therapeutically benefit some forms of PD. However, we must first learn whether restoring PINK1 function prevents degeneration in patients harboring PINK1 mutations, or whether boosting PINK1 function can offer protection in more common causes of PD. To test these hypotheses in preclinical rodent models of PD, we used kinetin triphosphate, a small-molecule that activates both wild-type and mutant forms of PINK1, which affects mitochondrial function and protects neural cells in culture. We chronically fed kinetin, the precursor of kinetin triphosphate, to PINK1-null rats in which PINK1 was reintroduced into their midbrain, and also to rodent models overexpressing α-synuclein. The highest tolerated dose of oral kinetin increased brain levels of kinetin for up to 6 months, without adversely affecting the survival of nigrostriatal dopamine neurons. However, there was no degeneration of midbrain dopamine neurons lacking PINK1, which precluded an assessment of neuroprotection and raised questions about the robustness of the PINK1 KO rat model of PD. In two rodent models of α-synuclein-induced toxicity, boosting PINK1 activity with oral kinetin provided no protective effects. Our results suggest that oral kinetin is unlikely to protect against α-synuclein toxicity, and thus fail to provide evidence that kinetin will protect in sporadic models of PD. Kinetin may protect in cases of PINK1 deficiency, but this possibility requires a more robust PINK1 KO model that can be validated by proof-of-principle genetic correction in adult animals.

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The Role of Mitochondrially Derived ATP in Synaptic Vesicle Recycling

Cited by 233 publications

References 62 publications

Limited distal organelles and synaptic function in extensive monoaminergic innervation

Limited distal organelles and synaptic function in extensive monoaminergic innervation

Miro1‐dependent mitochondrial positioning drives the rescaling of presynaptic Ca ²⁺ signals during homeostatic plasticity

Long-term oral kinetin does not protect against α-synuclein-induced neurodegeneration in rodent models of Parkinson's disease

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The Role of Mitochondrially Derived ATP in Synaptic Vesicle Recycling

Cited by 233 publications

References 62 publications

Limited distal organelles and synaptic function in extensive monoaminergic innervation

Limited distal organelles and synaptic function in extensive monoaminergic innervation

Miro1‐dependent mitochondrial positioning drives the rescaling of presynaptic Ca 2+ signals during homeostatic plasticity

Long-term oral kinetin does not protect against α-synuclein-induced neurodegeneration in rodent models of Parkinson's disease

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Miro1‐dependent mitochondrial positioning drives the rescaling of presynaptic Ca ²⁺ signals during homeostatic plasticity