Dataset Information

Synaptosomes: new vesicles for neuronal mitochondrial transplantation.

ABSTRACT:

Background

Mitochondrial dysfunction is a critical factor in the onset and progression of neurodegenerative diseases. Recently, mitochondrial transplantation has been advised as an innovative and attractive strategy to transfer and replace damaged mitochondria. Here we propose, for the first time, to use rat brain extracted synaptosomes, a subcellular fraction of isolated synaptic terminal that contains mitochondria, as mitochondrial delivery systems.

Results

Synaptosome preparation was validated by the presence of Synaptophysin and PSD95. Synaptosomes were characterized in terms of dimension, zeta potential, polydispersity index and number of particles/ml. Nile Red or CTX-FITCH labeled synaptosomes were internalized in LAN5 recipient cells by a mechanism involving specific protein-protein interaction, as demonstrated by loss of fusion ability after trypsin treatment and using different cell lines. The loading and release ability of the synaptosomes was proved by the presence of curcumin both into synaptosomes and LAN5 cells. The vitality of mitochondria transferred by Synaptosomes was demonstrated by the presence of Opa1, Fis1 and TOM40 mitochondrial proteins and JC-1 measurements. Further, synaptosomes deliver vital mitochondria into the cytoplasm of neuronal cells as demonstrated by microscopic images, increase of TOM 40, cytochrome c, Hexokinase II mitochondrial proteins, and presence of rat mitochondrial DNA. Finally, by using synaptosomes as a vehicle, healthy mitochondria restored mitochondrial function in cells containing rotenone or CCCp damaged mitochondria.

Conclusions

Taken together these results suggest that synaptosomes can be a natural vehicle for the delivery of molecules and organelles to neuronal cells. Further, the replacement of affected mitochondria with healthy ones could be a potential therapy for treating neuronal mitochondrial dysfunction-related diseases.

SUBMITTER: Picone P

PROVIDER: S-EPMC7789323 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Publications

Synaptosomes: new vesicles for neuronal mitochondrial transplantation.

Picone Pasquale P Porcelli Gaetana G Bavisotto Celeste Caruso CC Nuzzo Domenico D Galizzi Giacoma G Biagio Pier Luigi San PLS Bulone Donatella D Di Carlo Marta M

Journal of nanobiotechnology 20210106 1

<h4>Background</h4>Mitochondrial dysfunction is a critical factor in the onset and progression of neurodegenerative diseases. Recently, mitochondrial transplantation has been advised as an innovative and attractive strategy to transfer and replace damaged mitochondria. Here we propose, for the first time, to use rat brain extracted synaptosomes, a subcellular fraction of isolated synaptic terminal that contains mitochondria, as mitochondrial delivery systems.<h4>Results</h4>Synaptosome preparati ...[more]

PMID: 33407593

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Project description:BackgroundRepeated exposures to chronic stress can lead to long lasting negative behavioral and metabolic outcomes. Here, we aim to determine the impact of chronic stress and chronic low-level inflammation on behavior and synaptosomal metabolism.MethodsMale (n = 31) and female (n = 32) C57Bl/6 mice underwent chronic repeated predation stress or daily handling for two rounds of 15 consecutive days of exposure during the adolescent and early adult timeframes. Subsequently, mice were exposed to repeated lipopolysaccharide (LPS; 7.5 × 105 EU/kg) or saline injections every third day for eight weeks. Exploratory and social behaviors were assessed in the open field and social interaction tests prior to examination of learning and memory with the Barnes Maze. Mitochondrial function and morphology were assessed in synaptosomes post-mortem using the Cell Mito Stress test and Seahorse XFe24 analyzer, TEM, and western analysis, respectively. In addition, expression of TNF-α, IL-1ß, and ROMO1 were examined in the hippocampus and prefrontal cortex with Taqman qPCR. Circulating pro- and anti-inflammatory cytokines in the periphery were assessed using the MSD V-plex Proinflammatory Panel 1 following the first and last LPS injection as well as at the time of tissue collection. Circulating ROMO1 was assessed in terminal samples via ELISA.ResultsExposure to repeated predatory stress increased time spent in the corners of the open field, suggestive of anxiety-like behavior, in both males and females. There were no significant group differences in the social interaction test and minimal effects were evident in the Barnes maze. A history of chronic stress interacted with chronic LPS in male mice to lead to a deficit in synaptosomal respiration. Female mice were more sensitive to both chronic stress and chronic LPS such that either a history of chronic stress or chronic LPS exposure was sufficient to disrupt synaptosomal respiration in females. Both stress and chronic LPS were sufficient to increase inflammation and reactive oxygen in males centrally and peripherally. Females had increased markers of peripheral inflammation following acute LPS but no evidence of peripheral or central increases in inflammatory factors or reactive oxygen following chronic exposures.ConclusionCollectively, these data suggest that while metrics of inflammation and reactive oxygen are disrupted in males following chronic stress and chronic LPS, only the combined condition is sufficient to alter synaptosomal respiration. Conversely, although evidence of chronic inflammation or chronic elevation in reactive oxygen is absent, females demonstrate profound shifts in synaptosomal mitochondrial function with either a history of chronic stress or a history of chronic inflammation. These data highlight that different mechanisms are likely in play between the sexes and that sex differences in neural outcomes may be precipitated by sex-specific effects of life experiences on mitochondrial function in the synapse.

Dataset Information

Synaptosomes: new vesicles for neuronal mitochondrial transplantation.

Background

Results

Conclusions

Publications

Synaptosomes: new vesicles for neuronal mitochondrial transplantation.

Similar Datasets

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