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The toxicity of misfolded proteins and mitochondrial dysfunction are pivotal factors that promote age-associated functional neuronal decline and neurodegenerative disease1, 2. Accordingly, neurons invest considerable cellular resources in chaperones, protein degradation, autophagy and mitophagy to maintain proteostasis and mitochondrial quality3, 4...
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... studying age-associated dendritic restructuring in C. elegans neurons 7 , we noticed that fluorescent signals originating from neurons sometimes appeared situated outside of the cell in defined vesicle-like structures that we call exophers (Fig. 1a-c, Extended Data Fig. 1a-c, 2g). We first characterized exophers associated with the six gentle touch receptor neurons, for which cell bodies and dendrites are easily visualized. We found that exophers were comparable in size (average 3.8 μM) to neuronal somas (Extended Data Fig. 1d). The size of the vesicles, the morphological stages ...
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... studying age-associated dendritic restructuring in C. elegans neurons 7 , we noticed that fluorescent signals originating from neurons sometimes appeared situated outside of the cell in defined vesicle-like structures that we call exophers (Fig. 1a-c, Extended Data Fig. 1a-c, 2g). We first characterized exophers associated with the six gentle touch receptor neurons, for which cell bodies and dendrites are easily visualized. We found that exophers were comparable in size (average 3.8 μM) to neuronal somas (Extended Data Fig. 1d). The size of the vesicles, the morphological stages in their biogenesis (Fig. ...
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... first characterized exophers associated with the six gentle touch receptor neurons, for which cell bodies and dendrites are easily visualized. We found that exophers were comparable in size (average 3.8 μM) to neuronal somas (Extended Data Fig. 1d). The size of the vesicles, the morphological stages in their biogenesis (Fig. 1a-c), and the genetic requirements for their production (Extended Data Table 1a), distinguish them from much smaller exosomes (~30-100nm; Extended Data Table 2 compares exophers to characterized extracellular vesicles). ...
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... Data Fig. 1a-c, 2g). We first characterized exophers associated with the six gentle touch receptor neurons, for which cell bodies and dendrites are easily visualized. We found that exophers were comparable in size (average 3.8 μM) to neuronal somas (Extended Data Fig. 1d). The size of the vesicles, the morphological stages in their biogenesis (Fig. 1a-c), and the genetic requirements for their production (Extended Data Table 1a), distinguish them from much smaller exosomes (~30-100nm; Extended Data Table 2 compares exophers to characterized extracellular vesicles). Neuronal exophers do not appear to result from classical cell division: a) exophers did not stain with nuclear DNA ...
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... and the genetic requirements for their production (Extended Data Table 1a), distinguish them from much smaller exosomes (~30-100nm; Extended Data Table 2 compares exophers to characterized extracellular vesicles). Neuronal exophers do not appear to result from classical cell division: a) exophers did not stain with nuclear DNA indicator DAPI (Fig. 1b); b) cell division-inhibiting hydroxyurea 8 did not change exopher levels (n > 30 per trial, three trials); and c) RNAi-mediated disruption of cell cycle genes did not change exopher detection (Extended Data Table ...
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... found that exopher production is not restricted to a specific transgene reporter or line (examples in Fig. 1, Extended Data Fig. 1). Amphid neurons that are dye-filled due to openings to the outside environment 9 (Extended Data Fig. 1e, f) can produce exophers, establishing that exophers can form under native/physiological cellular conditions. Exopher production differs dramatically among the six touch receptor neurons, with ALMR producing ...
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... found that exopher production is not restricted to a specific transgene reporter or line (examples in Fig. 1, Extended Data Fig. 1). Amphid neurons that are dye-filled due to openings to the outside environment 9 (Extended Data Fig. 1e, f) can produce exophers, establishing that exophers can form under native/physiological cellular conditions. Exopher production differs dramatically among the six touch receptor neurons, with ALMR producing exophers most frequently ...
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... found that exopher production is not restricted to a specific transgene reporter or line (examples in Fig. 1, Extended Data Fig. 1). Amphid neurons that are dye-filled due to openings to the outside environment 9 (Extended Data Fig. 1e, f) can produce exophers, establishing that exophers can form under native/physiological cellular conditions. Exopher production differs dramatically among the six touch receptor neurons, with ALMR producing exophers most frequently (Fig. 1d). Multiple neuronal types can produce exophers, including dopaminergic PDE and CEP neurons ...
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... Fig. 1). Amphid neurons that are dye-filled due to openings to the outside environment 9 (Extended Data Fig. 1e, f) can produce exophers, establishing that exophers can form under native/physiological cellular conditions. Exopher production differs dramatically among the six touch receptor neurons, with ALMR producing exophers most frequently (Fig. 1d). Multiple neuronal types can produce exophers, including dopaminergic PDE and CEP neurons (Extended Data Fig. 1g, h), FLP neurons (not shown), sensory ASER neurons (Extended Data Fig. ...
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... f) can produce exophers, establishing that exophers can form under native/physiological cellular conditions. Exopher production differs dramatically among the six touch receptor neurons, with ALMR producing exophers most frequently (Fig. 1d). Multiple neuronal types can produce exophers, including dopaminergic PDE and CEP neurons (Extended Data Fig. 1g, h), FLP neurons (not shown), sensory ASER neurons (Extended Data Fig. ...
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... production differs dramatically among the six touch receptor neurons, with ALMR producing exophers most frequently (Fig. 1d). Multiple neuronal types can produce exophers, including dopaminergic PDE and CEP neurons (Extended Data Fig. 1g, h), FLP neurons (not shown), sensory ASER neurons (Extended Data Fig. 1i). ...
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... analyses (Supplemental Videos 1-2) revealed that exophers typically arise from the soma by asymmetrically amassing labeled protein to create a balloon-like extrusion via a pinching off event; the exopher compartment then moves outward from the neuronal cell body (extrusion ~15-100 minutes; Fig. 1a, Extended Data Fig. 1a). Plasma membrane reporter P mec-4 PH(plcDelta)::GFP (Extended Data Fig. 2a) and electron microscopy data (Extended Data Fig. 2) confirm that exophers are membrane-bound. Exophers can initially remain connected to the soma by a thin thread-like tube (Fig. 1c) that can allow transfer of tagged proteins and calcium ...
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... analyses (Supplemental Videos 1-2) revealed that exophers typically arise from the soma by asymmetrically amassing labeled protein to create a balloon-like extrusion via a pinching off event; the exopher compartment then moves outward from the neuronal cell body (extrusion ~15-100 minutes; Fig. 1a, Extended Data Fig. 1a). Plasma membrane reporter P mec-4 PH(plcDelta)::GFP (Extended Data Fig. 2a) and electron microscopy data (Extended Data Fig. 2) confirm that exophers are membrane-bound. Exophers can initially remain connected to the soma by a thin thread-like tube (Fig. 1c) that can allow transfer of tagged proteins and calcium into the attached ...
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... outward from the neuronal cell body (extrusion ~15-100 minutes; Fig. 1a, Extended Data Fig. 1a). Plasma membrane reporter P mec-4 PH(plcDelta)::GFP (Extended Data Fig. 2a) and electron microscopy data (Extended Data Fig. 2) confirm that exophers are membrane-bound. Exophers can initially remain connected to the soma by a thin thread-like tube (Fig. 1c) that can allow transfer of tagged proteins and calcium into the attached exopher compartment (Extended Data Fig. 1a, 3, Supplemental Video 2). Exophers ultimately disconnect from the originating neuronal soma (Extended Data Fig. ...
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... membrane reporter P mec-4 PH(plcDelta)::GFP (Extended Data Fig. 2a) and electron microscopy data (Extended Data Fig. 2) confirm that exophers are membrane-bound. Exophers can initially remain connected to the soma by a thin thread-like tube (Fig. 1c) that can allow transfer of tagged proteins and calcium into the attached exopher compartment (Extended Data Fig. 1a, 3, Supplemental Video 2). Exophers ultimately disconnect from the originating neuronal soma (Extended Data Fig. 3). ...
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... production occurs with a striking bimodal distribution over adult life: exophers are most commonly observed on adult days A2-A3, diminish in abundance A4-A8, and then reappear again later in life ~A10-A11 ( Fig. 2d; similar young adult pattern with dye-filled amphid neurons, Extended Data Fig. 1f; and with a 1 day earlier onset in an hsf-1 mutant, Extended Data Fig. 1j). The distinctive temporal production profile suggests that conditions permissive for exopher production exist in young adulthood but can then be limited or remain below a threshold until late adulthood. The coincidence of the early peak with a transition in C. ...
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... with a striking bimodal distribution over adult life: exophers are most commonly observed on adult days A2-A3, diminish in abundance A4-A8, and then reappear again later in life ~A10-A11 ( Fig. 2d; similar young adult pattern with dye-filled amphid neurons, Extended Data Fig. 1f; and with a 1 day earlier onset in an hsf-1 mutant, Extended Data Fig. 1j). The distinctive temporal production profile suggests that conditions permissive for exopher production exist in young adulthood but can then be limited or remain below a threshold until late adulthood. The coincidence of the early peak with a transition in C. elegans young adult proteostasis management [12][13][14] suggests the first ...
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... than inducing neuronal death or dysfunction, exopher-genesis appears beneficial. First, in hundreds of longitudinal observations, we did not observe neuronal loss after exopher production: exophers are distinct from apoptotic bodies in their biogenesis (Fig. 1a, Extended Data Fig. 1a), and the soma of an exopher-producing neuron retains normal ultrastructural features (Extended Data Fig. 2e). Second, the relative functionality of proteotoxically-stressed neurons that have generated exophers is increased over neurons that did not extrude exophers. In blinded studies in a line expressing ...
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... than inducing neuronal death or dysfunction, exopher-genesis appears beneficial. First, in hundreds of longitudinal observations, we did not observe neuronal loss after exopher production: exophers are distinct from apoptotic bodies in their biogenesis (Fig. 1a, Extended Data Fig. 1a), and the soma of an exopher-producing neuron retains normal ultrastructural features (Extended Data Fig. 2e). Second, the relative functionality of proteotoxically-stressed neurons that have generated exophers is increased over neurons that did not extrude exophers. In blinded studies in a line expressing Q128CFP, which progressively ...
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... for mitochondrial quality control: mitochondrial expulsion. The mito-expulsion we report in C. elegans touch neurons has a striking mammalian counterpart: mouse mitochondria originating in retinal ganglion cells can be extruded into neighboring astrocytes for degradation 6 (with some intriguingly similar morphology to C. elegans exophers; see Fig. 1e of ref. 6). Although further study will be required to definitively establish the health status and fates of transferred mitochondria in the C. elegans model, it is tempting to speculate that transcellular degradation of mitochondria may be a more broadly utilized mechanism of mitochondrial quality control than currently appreciated, ...
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... to Web version on PubMed Central for supplementary material. days and between strains was significant (***P < 0.001). A similar early adulthood peak occurs in dye-filled amphid neurons (Extended Data Fig. 1f) and in the hsf-1 mutant (Extended Data Fig. 1j). e. Multiple early visible aggregates predict later exopher formation. On adult day 1, we segregated animals by number of mCherry aggregates (1 Ag vs ≥ 2 Ag) in the ALMR soma and scored for exophers on adult day 2. 5 trials, n > 130 total per condition, ***P < ...
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... We find that autophagosome contents are dumped from neurons harboring hyperactive LRRK2, raising the question of what happens to the released cellular waste, e.g., mitochondria, in vivo? Mitochondrial exchange between neighboring cells, including neurons and adjacent glia, has been described by multiple groups (22,23,36,60,61) Tunneling nanotubes can serve as one . CC-BY 4.0 International license available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. ...
Autophagic dysfunction is a hallmark of neurodegenerative disease, leaving neurons vulnerable to the accumulation of damaged organelles and proteins. However, the late onset of diseases suggests that compensatory quality control mechanisms may be engaged to delay the deleterious effects induced by compromised autophagy. Neurons expressing common familial Parkinson’s disease (PD)-associated mutations in LRRK2 kinase exhibit defective autophagy. Here, we demonstrate that both primary murine neurons and human iPSC-derived neurons harboring pathogenic LRRK2 upregulate the secretion of extracellular vesicles. We used unbiased proteomics to characterize the secretome of LRRK2 G2019S neurons and found that autophagic cargos including mitochondrial proteins were enriched. Based on these observations, we hypothesized that autophagosomes are rerouted toward secretion when cell-autonomous degradation is compromised, likely to mediate clearance of undegraded cellular waste. Immunoblotting confirmed the release of autophagic cargos and immunocytochemistry demonstrated that secretory autophagy was upregulated in LRRK2 G2019S neurons. We also found that LRRK2 G2019S neurons upregulate the release of exosomes containing miRNAs. Live-cell imaging confirmed that this upregulation of exosomal release was dependent on hyperactive LRRK2 activity, while pharmacological experiments indicate that this release staves off apoptosis. Finally, we show that markers of both vesicle populations are upregulated in plasma from mice expressing pathogenic LRRK2. In sum, we find that neurons expressing pathogenic LRRK2 upregulate the compensatory release of secreted autophagosomes and exosomes, to mediate waste disposal and transcellular communication, respectively. We propose that this increased secretion contributes to the maintenance of cellular homeostasis, delaying neurodegenerative disease progression over the short term while potentially contributing to increased neuroinflammation over the longer term.
SIGNIFICANCE
A hallmark feature of many neurodegenerative diseases is autophagy dysfunction, resulting in the accumulation of damaged proteins and organelles that is detrimental to neuronal health. The late onset of neurodegenerative diseases, however, suggests alternative quality control mechanisms may delay neuronal degeneration. Here, we demonstrate that neurons expressing a Parkinson’s Disease-causing mutation upregulate the release of two extracellular vesicle populations. First, we observe the increased expulsion of secreted autophagosomes to mediate cellular waste disposal. Second, we observe the increased release of exosomes, likely to facilitate transcellular communication. Thus, we propose that increases in secretory autophagy and exosome release are a homeostatic response in neurons undergoing chronic stress.
... More recently, the generation and clearance of large EVs containing dysfunctional mitochondria (i.e. exophers and migrasomes) from distinct cell types such as cardiomyocytes, neurons and migrating cells were demonstrated as an alternative waste disposal mechanism that maintains tissue homoeostasis, limits inflammation and aids organogenesis 9,10,[29][30][31] . Furthermore, the release of EVs containing healthy mitochondria from spermatid is also a critical process for normal sperm development 32 . ...
... EV analysis by both conventional and imaging flow cytometry approaches demonstrated that Flk1-GFP + EVs exposed the characteristic cell death marker and 'eat-me' signal, phosphatidylserine (PtdSer) (Fig. 1p, q). These data suggest that Flk1-GFP + EVs may represent either endothelial cell-derived apoptotic bodies (typically >1 μm, nuclear DNA +/− , PtdSer + , formed in an apoptosisdependent manner 11 ) and/or exophers (~3 μm, mitochondria rich, PtdSer + , formed in an autophagy-dependent manner 10,31 ). To examine whether Flk1-GFP + EVs could be derived from either apoptotic and/or autophagic cells, we determined the level of homoeostatic endothelial cell apoptosis by staining for cleaved caspase 3 in long bone sections using combined confocal multiphoton microscopy. ...
... Collectively, these data demonstrate that endothelial cells can generate large, mitochondriacontaining EVs under homoeostatic settings. As markers for apoptotic bodies and exophers are not well described, EV characteristics such as size, PtdSer exposure, active caspase 3/7 and mitochondria content cannot be used to distinguish these large EV subsets 10,31,[48][49][50] . Thus, in line with the MISEV2023 guidelines 51 , we adopted the use of the operational term large endothelial cell-derived EVs to describe EVs being studied herein. ...
Endothelial cells are integral components of all vasculature within complex organisms. As they line the blood vessel wall, endothelial cells are constantly exposed to a variety of molecular factors and shear force that can induce cellular damage and stress. However, how endothelial cells are removed or eliminate unwanted cellular contents, remains unclear. The generation of large extracellular vesicles (EVs) has emerged as a key mechanism for the removal of cellular waste from cells that are dying or stressed. Here, we used intravital microscopy of the bone marrow to directly measure the kinetics of EV formation from endothelial cells in vivo under homoeostatic and malignant conditions. These large EVs are mitochondria-rich, expose the ‘eat me’ signal phosphatidylserine, and can interact with immune cell populations as a potential clearance mechanism. Elevated levels of circulating EVs correlates with degradation of the bone marrow vasculature caused by acute myeloid leukaemia. Together, our study provides in vivo spatio-temporal characterization of EV formation in the murine vasculature and suggests that circulating, large endothelial cell-derived EVs can provide a snapshot of vascular damage at distal sites.
... Ectosomes bud directly from the plasma membrane, and apoptotic EVs form during apoptosis by cell fragmentation. Recently, more subtypes have been discovered, such as migrasomes [13] and exophers [14]; their capacity to specifically deliver molecules for therapeutic purposes is yet to be discovered ( Figure 1). The EVs mentioned below mostly represent particles <1000 nm in diameter, like exosomes and the classic type of ectosomes a.k.a microvesicles. ...
Extracellular vesicles (EVs) are natural carriers of biomolecules that play a crucial role in cell-to-cell communication and tissue homeostasis under normal and pathological conditions, including inflammatory diseases and cancer. Since the discovery of the pro-regenerative and immune-modulating properties of EVs, EV-based therapeutics have entered clinical trials for conditions such as myocardial infarction and autoimmune diseases, among others. Due to their unique advantages—such as superior bioavailability, substantial packaging capacity, and the ability to traverse biological barriers—EVs are regarded as a promising platform for targeted drug delivery. However, achieving sufficient accumulation of therapeutic agents at the target site necessitates a larger quantity of EVs per dose compared to using EVs as standalone drugs. This challenge can be addressed by administering larger doses of EVs, increasing the drug dosage per administration, or enhancing the selective accumulation of EVs at target cells. In this review, we will discuss methods to improve the isolation and purification of EVs, approaches to enhance cargo packaging—including proteins, RNAs, and small-molecule drugs—and technologies for displaying targeting ligands on the surface of EVs to facilitate improved targeting. Ultimately, this guide can be applied to the development of novel classes of EV-based therapeutics and to overcoming existing technological challenges.
... These include alternative vesicular pathways like LC3-associated phagocytosis and LC3-associated endocytosis, as well as unconventional secretory pathways involving the formation of extracellular vesicles. While the role of these noncanonical autophagy pathways in aging and age-related diseases remains to be fully elucidated (reviewed in [42,66]), a recent study of C. elegans showed that reduced levels of autophagy genes involved in ATG8/LC3 conjugation lead to the formation of so-called exophers, which are large neuronal extrusions [67,68]. ...
... Additional work is clearly required to investigate the molecular dynamics of such decline. As inhibition of early-acting autophagy genes involved in autophagy initiation in C. elegans neurons causes expulsion of cellular cargo in secretory vesicles [67,68], reduced autophagic degradation may lead to increased noncanonical functions of autophagy proteins. Whether stalled autophagy in one tissue affects autophagy and proteostasis in other tissues via inter-tissue communication still has to be investigated. ...
Macroautophagy (hereafter autophagy) is a cellular recycling process that degrades cytoplasmic components, such as protein aggregates and mitochondria, and is associated with longevity and health in multiple organisms. While mounting evidence supports that autophagy declines with age, the underlying molecular mechanisms remain unclear. Since autophagy is a complex, multistep process, orchestrated by more than 40 autophagy-related proteins with tissue-specific expression patterns and context-dependent regulation, it is challenging to determine how autophagy fails with age. In this review, we describe the individual steps of the autophagy process and summarize the age-dependent molecular changes reported to occur in specific steps of the pathway that could impact autophagy. Moreover, we describe how genetic manipulations of autophagy-related genes can affect lifespan and healthspan through studies in model organisms and age-related disease models. Understanding the age-related changes in each step of the autophagy process may prove useful in developing approaches to prevent autophagy decline and help combat a number of age-related diseases with dysregulated autophagy.
... Eukaryotic cells have innate pathways for clearing misfolded, malfunctioning, aged, or aggregated proteins (Wen et al., 2023). These include refolding proteins into their normal physiological conformations, degrading proteins utilizing the ubiquitin-proteasome or autophagy-lysosome systems, asymmetric cell division (ACD), or exocytosis of aggregated protein via the extrusion of exosomes or exophers (Tyedmers et al., 2010;Dikic, 2017;Melentijevic et al., 2017;Mogk et al., 2018;Pohl and Dikic, 2019;Nicolas-Avila et al., 2020;FIGURE 2 Loss of dopaminergic neurons in the substantia nigra lead to interruption of dopamine pathways in the brain. Figure was created using BioRender.com. ...
An unprecedented extension of life expectancy observed during the past century drastically increased the number of patients diagnosed with Parkinson’s diseases (PD) worldwide. Estimated costs of PD alone reached $52 billion per year, making effective neuroprotective treatments an urgent and unmet need. Current treatments of both AD and PD focus on mitigating the symptoms associated with these pathologies and are not neuroprotective. In this review, we discuss the most advanced therapeutic strategies that can be used to treat PD. We also critically review the shift of the therapeutic paradigm from a small molecule-based inhibition of protein aggregation to the utilization of natural degradation pathways and immune cells that are capable of degrading toxic amyloid deposits in the brain of PD patients.
... Nevertheless, since these categories cannot be distinguished in bulk purified EV preparations, the field has proposed the use of the terms large EVs (lEVs) and small EVs (sEVs) in the absence of other information about biogenesis pathways. The largest categories of lEVs are apoptotic bodies (500 nm-5um) which originate from apoptotic cells [25], migrasomes (300 nm-3um) which originate from the trail left by migratory cells [26], oncosomes (1-10um) which originate from cancer cells [27], exophers (1-50um) which are large vesicles that can contain organelles released from C. elegans neurons [28], and microvesicles (100-1,000 nm) which constitute a heterogeneous group of vesicles that directly bud from the plasma membrane, including a subset of sEVs [29] (Figure 1). The best characterized sublass of sEVs is exosomes (50-150 nm) that are derived from the endocytic system, distinct from sEVs released directly from the plasma membrane. ...
Extracellular vesicles and nanoparticles (EVPs) are now recognized as a novel form of cell–cell communication. All cells release a wide array of heterogeneous EVPs with distinct protein, lipid, and RNA content, dependent on the pathophysiological state of the donor cell. The overall cargo content in EVPs is not equivalent to cellular levels, implying a regulated pathway for selection and export. In cancer, release and uptake of EVPs within the tumour microenvironment can influence growth, proliferation, invasiveness, and immune evasion. Secreted EVPs can also have distant, systemic effects that can promote metastasis. Here, we review current knowledge of EVP biogenesis and cargo selection with a focus on the role that extracellular RNA plays in oncogenesis and metastasis. Almost all subtypes of RNA have been identified in EVPs, with miRNAs being the best characterized. We review the roles of specific miRNAs that have been detected in EVPs and that play a role in oncogenesis and metastasis.
... Exophers contain organelles, large protein complexes, and other components, and they play a role in the clearance of damaged, degraded, or aggregated material as well as dysfunctional mitochondria. Studies have demonstrated that exophers play a crucial role in neurological pathologies, as evidenced by research conducted by Melentijevic et al. (2017) and Arnold et al. (2023) [33,34]. Limited evidence is available regarding the involvement of exophers in tumors. ...
... Exophers contain organelles, large protein complexes, and other components, and they play a role in the clearance of damaged, degraded, or aggregated material as well as dysfunctional mitochondria. Studies have demonstrated that exophers play a crucial role in neurological pathologies, as evidenced by research conducted by Melentijevic et al. (2017) and Arnold et al. (2023) [33,34]. Limited evidence is available regarding the involvement of exophers in tumors. ...
Cancer poses a significant public health challenge worldwide, and timely screening has the potential to mitigate cancer progression and reduce mortality rates. Currently, early identification of most tumors relies on imaging techniques and tissue biopsies. However, the use of low-cost, highly sensitive, non-invasive detection methods for early cancer screening has become more attractive. Extracellular Vesicles (EVs) released by all living cells contain distinctive biological components, such as nucleic acids, proteins, and lipids. These vesicles play crucial roles in the tumor microenvironment and intercellular communication during tumor progression, rendering liquid biopsy a particularly suitable method for diagnosis. Nevertheless, challenges related to purification methods and validation of efficacy currently hinder its widespread clinical implementation. These limitations underscore the importance of refining isolation techniques and conducting comprehensive investigations on EVs. This study seeks to evaluate the potential of liquid biopsy utilizing blood-derived EVs as a practical, cost-effective, and secure approach for early cancer detection.
... Scale bars, 10 µm. to cytosol, however, our data show that even small amount of accumulation of α-Syn in mitochondria could significantly damage mitochondrial functions. In C. elegans, neurons can dispose mitochondria and protein aggregates in exophers 42 . It will be interesting to determine if there is a similar mechanism in mammals that would help remove α-Syn-containing mitochondria in a non-cell-autonomous fashion, when mitophagy failed to clear them in neurons. ...
Parkinson’s disease (PD) is a progressive neurodegenerative disease characterized by mitochondrial dysfunction and accumulation of alpha-synuclein (α-Syn)-containing protein aggregates known as Lewy bodies (LB). Here, we investigated the entry of α-Syn into mitochondria to cause mitochondrial dysfunction and loss of cellular fitness in vivo. We show that α-Syn expressed in yeast and human cells is constitutively imported into mitochondria. In a transgenic mouse model, the level of endogenous α-Syn accumulation in mitochondria of dopaminergic neurons and microglia increases with age. The imported α-Syn is degraded by conserved mitochondrial proteases, most notably NLN and PITRM1 (Prd1 and Cym1 in yeast, respectively). α-Syn in the mitochondrial matrix that is not degraded interacts with respiratory chain complexes, leading to loss of mitochondrial DNA (mtDNA), mitochondrial membrane potential and cellular fitness decline. Importantly, enhancing mitochondrial proteolysis by increasing levels of specific proteases alleviated these defects in yeast, human cells, and a PD model of mouse primary neurons. Together, our results provide a direct link between α-synuclein-mediated cellular toxicity and its import into mitochondria and reveal potential therapeutic targets for the treatment of α-synucleinopathies.
... Therefore, migrating cells necessarily require additional mechanisms to mitigate this higher mitochondrial stress burden. Mitochondrial shedding contributes to mitochondrial quality control (Melentijevic et al., 2017). Migrasomes can regulate the quality of mitochondria, thereby maintaining intracellular mitochondrial homeostasis by clearing out damaged mitochondria (Jiao et al., 2021) and avoiding the adverse effects caused by the accumulation of damaged mitochondria, such as cytochrome C release from mitochondria and subsequent caspase activation (Jiang and Wang, 2004;Bock and Tait, 2020). ...
Migrasomes are organelles produced by migrating cells that form on retraction fibers and are released during cell migration. Migrasomes are involved in physiological and pathological processes such as intercellular communication, cell homeostasis maintenance, signal transduction, disease occurrence and development, and cancer metastasis. In addition, methods and techniques for studying migrasomes are constantly evolving. Here, we review the discovery, formation process, regulation, and known functions of migrasomes, summarize the commonly used specific markers of migrasomes, and the methods for observing migrasomes. Meanwhile, this review also discusses the potential applications of migrasomes in physiological processes, disease diagnosis, treatment, and prognosis, and looks forward to their wider application in biomedicine. In addition, the study of migrasomes will also reveal a new perspective on the mechanism of intercellular communication and promote the further development of life science.
... Mitochondrial transplantation/mitochondrial transfer a therapeutic modality that aims to enhance cellular function and mitigate damage by replacing damaged mitochondria with healthy ones [222][223][224]. This approach entails the isolation of functional mitochondria, which are then introduced into the damaged tissue. ...
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta region of the midbrain and the formation of intracellular protein aggregates known as Lewy bodies, of which a major component is the protein α-synuclein. Several studies have suggested that mitochondria play a central role in the pathogenesis of PD, encompassing both familial and sporadic forms of the disease. Mitochondrial dysfunction is attributed to bioenergetic impairment, increased oxidative stress, damage to mitochondrial DNA, and alteration in mitochondrial morphology. These alterations may contribute to improper functioning of the central nervous system and ultimately lead to neurodegeneration. The perturbation of mitochondrial function makes it a potential target, worthy of exploration for neuroprotective therapies and to improve mitochondrial health in PD. Thus, in the current review, we provide an update on mitochondria-based therapeutic approaches toward α-synucleinopathies in PD.
