Mitochondria at the neuronal presynapse in health and disease

Devine, Michael J.; Kittler, Josef T.

doi:10.1038/nrn.2017.170

Cited by 472 publications

(391 citation statements)

References 228 publications

(268 reference statements)

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“…; Smith et al . ; Devine & Kittler, ). Pharmacological approaches have shown that mitochondria can regulate short‐term plasticity by adjusting Ca 2+ ‐dependent neurotransmitter release and synaptic vesicle recycling, and act to fulfil bioenergetic demands of the synapse by maintaining ATP during intense synaptic activity (Alnaes & Rahamimoff, ; Tang & Zucker, ; Li et al .…”

Section: Resultsmentioning

confidence: 99%

“…The ability of a synapse to successfully stimulate its postsynaptic accomplice depends on many presynaptic factors: calcium concentration, efficacy of fusion proteins for exocytosis, number of vesicles primed for release, and availability of cellular energy to fuel these processes. Using the calyx of Held as a model for examining presynaptic function, we hope to contribute to a greater mechanistic understanding of the synaptic basis of neurological and neurodegenerative diseases where dysregulation of mitochondrial dynamics and function is a likely culprit (Devine & Kittler, ). Here, we show DRP1 loss from the presynaptic compartment results in altered mitochondrial morphology and severe defects in multiple facets of synapse physiology.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Presynaptic loss of dynamin‐related protein 1 impairs synaptic vesicle release and recycling at the mouse calyx of Held

Singh

Denny

Smith

et al. 2018

The Journal of Physiology

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Key points This study characterizes the mechanisms underlying defects in synaptic transmission when dynamin‐related protein 1 (DRP1) is genetically eliminated. Viral‐mediated knockout of DRP1 from the presynaptic terminal at the mouse calyx of Held increased initial release probability, reduced the size of the synaptic vesicle recycling pool and impaired synaptic vesicle recycling. Transmission defects could be partially restored by increasing the intracellular calcium buffering capacity with EGTA‐AM, implying close coupling of Ca2+ channels to synaptic vesicles was compromised. Acute restoration of ATP to physiological levels in the presynaptic terminal did not reverse the synaptic defects. Loss of DRP1 impairs mitochondrial morphology in the presynaptic terminal, which in turn seems to arrest synaptic maturation. Abstract Impaired mitochondrial biogenesis and function is implicated in many neurodegenerative diseases, and likely affects synaptic neurotransmission prior to cellular loss. Dynamin‐related protein 1 (DRP1) is essential for mitochondrial fission and is disrupted in neurodegenerative disease. In this study, we used the mouse calyx of Held synapse as a model to investigate the impact of presynaptic DRP1 loss on synaptic vesicle (SV) recycling and sustained neurotransmission. In vivo viral expression of Cre recombinase in ventral cochlear neurons of floxed‐DRP1 mice generated a presynaptic‐specific DRP1 knockout (DRP1‐preKO), where the innervated postsynaptic cell was unperturbed. Confocal reconstruction of the calyx terminal suggested SV clusters and mitochondrial content were disrupted, and presynaptic terminal volume was decreased. Using postsynaptic voltage‐clamp recordings, we found that DRP1‐preKO synapses had larger evoked responses at low frequency stimulation. DRP1‐preKO synapses also had profoundly altered short‐term plasticity, due to defects in SV recycling. Readily releasable pool size, estimated with high‐frequency trains, was dramatically reduced in DRP1‐preKO synapses, suggesting an important role for DRP1 in maintenance of release‐competent SVs at the presynaptic terminal. Presynaptic Ca2+ accumulation in the terminal was also enhanced in DRP1‐preKO synapses. Synaptic transmission defects could be partially rescued with EGTA‐AM, indicating close coupling of Ca2+ channels to SV distance normally found in mature terminals may be compromised by DRP1‐preKO. Using paired recordings of the presynaptic and postsynaptic compartments, recycling defects could not be reversed by acute dialysis of ATP into the calyx terminals. Taken together, our results implicate a requirement for mitochondrial fission to coordinate postnatal synapse maturation.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Presynaptic loss of dynamin‐related protein 1 impairs synaptic vesicle release and recycling at the mouse calyx of Held

Singh

Denny

Smith

et al. 2018

The Journal of Physiology

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“…54,55 Particularly, these cells secret proinflammatory cytokines called senescence-associated secretory phenotype (SASP), which can accelerate the cells' further senescence (autocrine effect) or induce other cells' senescence (paracrine effect). 61,62 Kwon et al 63 demonstrated that mitochondria regulated presynaptic calcium homeostasis and thus in turn controlled neurotransmitter release. 59,60 Mitochondria can affect synapse activities and instigate abnormal transportation of neurotransmitters.…”

Section: Mitochondria In Depressionmentioning

confidence: 99%

Mitochondria could be a potential key mediator linking the intestinal microbiota to depression

Chen¹,

Vitetta

2019

J of Cellular Biochemistry

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The intestinal microbiota has been reported to affect depression, a common mental condition with severe health‐related consequences. However, what mediates the effect of the intestinal microbiota on depression has not been well elucidated. We summarize the roles of the mitochondria in eliciting beneficial effects on the gut microbiota to ameliorate symptoms of depression. It is well known that mitochondria play a key role in depression. An important pathogenic factor, namely inflammatory response, may adversely impact mitochondrial functionality to maintain cellular homeostasis. Dysfunction of mitochondria not only affects neuronal function but also reduces neuron cell numbers. We posit that the intestinal microbiota could affect neuronal mitochondrial function through short‐chain fatty acids such as butyrate. Brain inflammatory processes could also be affected through the modulation of gut permeability and blood lipopolysaccharide levels. Aberrant mitochondria functionality coupled to adverse cellular homeostasis could be a key mediator for the effect of the intestinal microbiota on the progression of depression.

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“…Pre‐synaptic mitochondrial abundance can be fine‐tuned owing to dynamic anterograde/retrograde trafficking. As Devine and Kittler review some neurons are devoid of pre‐synaptic mitochondria. Perhaps their absence masks synapse pruning, provided mitochondria can quickly re‐populate synapses to support neuronal activity .…”

Section: Potential Strategies For Regulating Mitochondrial O2−/h2o2mentioning

confidence: 99%

Synapse Pruning: Mitochondrial ROS with Their Hands on the Shears

Cobley

2018

BioEssays

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No overarching hypotheses tie the basic mechanisms of mitochondrial reactive oxygen species (ROS) production to activity dependent synapse pruning-a fundamental biological process in health and disease. Neuronal activity divergently regulates mitochondrial ROS: activity decreases whereas inactivity increases their production, respectively. Placing mitochondrial ROS as innate synaptic activity sentinels informs the novel hypothesis that: (1) at an inactive synapse, increased mitochondrial ROS production initiates intrinsic apoptosis dependent pruning; and (2) at an active synapse, decreased mitochondrial ROS production masks intrinsic apoptosis dependent pruning. Immature antioxidant defense may enable the developing brain to harness mitochondrial ROS to prune weak synapses. Beyond development, endogenous antioxidant defense constrains mitochondrial (ROS) to mask pruning. Unwanted age-related synapse loss may arise when mitochondrial ROS aberrantly recapitulate developmental pruning. Placing mitochondrial ROS with their hands on the shears is beneficial in early but deleterious in later life.

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Mitochondria at the neuronal presynapse in health and disease

Cited by 472 publications

References 228 publications

Presynaptic loss of dynamin‐related protein 1 impairs synaptic vesicle release and recycling at the mouse calyx of Held

Presynaptic loss of dynamin‐related protein 1 impairs synaptic vesicle release and recycling at the mouse calyx of Held

Mitochondria could be a potential key mediator linking the intestinal microbiota to depression

Synapse Pruning: Mitochondrial ROS with Their Hands on the Shears

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