bims-mitrat 2024-05-19 papers

bims-mitrat

Biomed News

on Mitochondrial Transplantation and Transfer

Issue of 2024‒05‒19
nineteen papers selected by
Gökhan Burçin Kubat, Gulhane Health Sciences Institute

Small Extracellular Vesicle Signaling and Mitochondrial Transfer Reprograms T Helper Cell Function in Human Asthma.
Mitochondrial dysfunction: mechanisms and advances in therapy.
Skeletal Muscle Mitochondrial Dysfunction Mediated by Pseudomonas aeruginosa Quorum Sensing Transcription Factor MvfR: Reversing Effects with Anti-MvfR and Mitochondrial-Targeted Compounds.
Mitochondrial heterogeneity and adaptations to cellular needs.
Mitochondria-Derived Vesicles, Sterile Inflammation, and Pyroptosis in Liver Cancer: Partners in Crime or Innocent Bystanders?
ESCRT disruption provides evidence against signaling functions for synaptic exosomes.
Extracellular vesicles as nanotheranostic platforms for targeted neurological disorder interventions.
Extracellular vesicles as human therapeutics: A scoping review of the literature.
Mechanical stretch preconditioned adipose-derived stem cells elicit polarization of anti-inflammatory M2-like macrophages and improve chronic wound healing.
The emerging role of extracellular vesicles in the diagnosis and treatment of autism spectrum disorders.
Mitochondrial function and gastrointestinal diseases.
Extracellular vesicles from senescent mesenchymal stromal cells are defective and cannot prevent osteoarthritis.
Muscle Psn gene combined with exercise contribute to healthy aging of skeletal muscle and lifespan by adaptively regulating Sirt1/PGC-1α and arm pathway.
Mitogenome architecture supports the non-monophyly of the cosmopolitan parasitoid wasp subfamily Doryctinae (Hymenoptera: Braconidae) recovered by nuclear and mitochondrial phylogenomics.
Regulation of Vascular Endothelial Integrity by Mesenchymal Stem Cell Extracellular Vesicles after Hemorrhagic Shock and Trauma.
Rapid Assessment of Biomarkers on Single Extracellular Vesicles Using 'Catch and Display' on Ultrathin Nanoporous Silicon Nitride Membranes.
The Role of Protein S-Nitrosylation in Mitochondrial Quality Control in Central Nervous System Diseases.
Integrated proteomic, phosphoproteomic, and N-glycoproteomic analyses of small extracellular vesicles from C2C12 myoblasts identify specific PTM patterns in ligand-receptor interactions.
Neutrophil-macrophage communication via extracellular vesicle transfer promotes itaconate accumulation and ameliorates cytokine storm syndrome.

bioRxiv. 2024 May 03. pii: 2024.04.30.589227. [Epub ahead of print]

Small Extracellular Vesicle Signaling and Mitochondrial Transfer Reprograms T Helper Cell Function in Human Asthma.

Kenneth P Hough, Jennifer L Trevor, Balu K Chacko, John G Strenkowski, Yong Wang, Kayla F Goliwas, Nathaniel B Bone, Young-Il Kim, Renita Holmes, Shia Vang, Alexandra Pritchard, Jay Chin, Sandeep Bodduluri, Veena B Antony, Sultan Tousif, Mohammad S Athar, Diptiman Chanda, Kasturi Mitra, Jaroslaw Zmijewski, Jianhua Zhang, Steven R Duncan, Victor J Thannickal, Susanne Gabrielsson, Victor M Darley-Usmar, Jessy S Deshane.

RATIONALE: Asthma is a chronic inflammatory disease of the airways that involves crosstalk between myeloid-derived regulatory cells (MDRCs) and CD4+ T cells. Although small extracellular vesicles (sEVs) are known to mediate cell-cell communication, the role of sEV signaling via mitochondria in perpetuating asthmatic airway inflammation is unknown.OBJECTIVES: We investigated the effects of MDRC-derived exosomes on dysregulated T cell responses in asthmatics.
METHODS: Small extracellular vesicles isolated from bronchoalveolar lavage fluid or airway MDRCs of mild to moderate asthmatics or healthy controls were co-cultured with autologous peripheral and airway CD4+ T lymphocytes. sEV internalization, sEV-mediated transfer of mitochondria targeted GFP to T cells, sEV mitochondrial signaling, and subsequent activation, proliferation and polarization of CD4+ T lymphocytes to Th1, Th2 and Th17 subsets were assessed.
MEASUREMENTS AND MAIN RESULTS: Airway MDRC-derived sEVs from asthmatics mediated T cell receptor engagement and transfer of mitochondria that induced antigen-specific activation and polarization into Th17 and Th2 cells, drivers of chronic airway inflammation in asthma. CD4+ T cells internalized sEVs containing mitochondria predominantly by membrane fusion, and blocking mitochondrial oxidant signaling in MDRC-derived exosomes mitigated T cell activation. Reactive oxygen species-mediated signaling that elicited T cell activation in asthmatics was sEV-dependent. A Drp1-dependent mitochondrial fission in pro-inflammatory MDRCs promoted mitochondrial packaging within sEVs, which then co-localized with the polarized actin cytoskeleton and mitochondrial networks in the organized immune synapse of recipient T cells.
CONCLUSIONS: Our studies indicate a previously unrecognized role for mitochondrial fission and exosomal mitochondrial transfer in dysregulated T cell activation and Th cell differentiation in asthma which could constitute a novel therapeutic target.

DOI: https://doi.org/10.1101/2024.04.30.589227
Signal Transduct Target Ther. 2024 May 15. 9(1): 124

Mitochondrial dysfunction: mechanisms and advances in therapy.

Yao Zong, Hao Li, Peng Liao, Long Chen, Yao Pan, Yongqiang Zheng, Changqing Zhang, Delin Liu, Minghao Zheng, Junjie Gao.

Mitochondria, with their intricate networks of functions and information processing, are pivotal in both health regulation and disease progression. Particularly, mitochondrial dysfunctions are identified in many common pathologies, including cardiovascular diseases, neurodegeneration, metabolic syndrome, and cancer. However, the multifaceted nature and elusive phenotypic threshold of mitochondrial dysfunction complicate our understanding of their contributions to diseases. Nonetheless, these complexities do not prevent mitochondria from being among the most important therapeutic targets. In recent years, strategies targeting mitochondrial dysfunction have continuously emerged and transitioned to clinical trials. Advanced intervention such as using healthy mitochondria to replenish or replace damaged mitochondria, has shown promise in preclinical trials of various diseases. Mitochondrial components, including mtDNA, mitochondria-located microRNA, and associated proteins can be potential therapeutic agents to augment mitochondrial function in immunometabolic diseases and tissue injuries. Here, we review current knowledge of mitochondrial pathophysiology in concrete examples of common diseases. We also summarize current strategies to treat mitochondrial dysfunction from the perspective of dietary supplements and targeted therapies, as well as the clinical translational situation of related pharmacology agents. Finally, this review discusses the innovations and potential applications of mitochondrial transplantation as an advanced and promising treatment.

DOI: https://doi.org/10.1038/s41392-024-01839-8
bioRxiv. 2024 May 05. pii: 2024.05.03.592480. [Epub ahead of print]

Skeletal Muscle Mitochondrial Dysfunction Mediated by Pseudomonas aeruginosa Quorum Sensing Transcription Factor MvfR: Reversing Effects with Anti-MvfR and Mitochondrial-Targeted Compounds.

Shifu Aggarwal, Vijay Singh, Arijit Chakraborty, Sujin Cha, Alexandra Dimitriou, Claire de Crescenzo, Olivia Izikson, Lucy Yu, Roberto Plebani, A Aria Tzika, Laurence G Rahme.

Sepsis and chronic infections with Pseudomonas aeruginosa, a leading "ESKAPE" bacterial pathogen, are associated with increased morbidity and mortality and skeletal muscle atrophy. The actions of this pathogen on skeletal muscle remain poorly understood. In skeletal muscle, mitochondria serve as a crucial energy source, which may be perturbed by infection. Here, using the well-established backburn and infection model of murine P. aeruginosa infection, we deciphered the systemic impact of the quorum sensing (QS) transcription factor MvfR by interrogating five days post-infection its effect on mitochondrial-related functions in the gastrocnemius skeletal muscle and the outcome of the pharmacological inhibition of MvfR function and that of the mitochondrial-targeted peptide, Szeto-Schiller 31 (SS-31). Our findings show that the MvfR perturbs ATP generation, oxidative phosphorylation (OXPHOS), and antioxidant response, elevates the production of reactive oxygen species, and promotes oxidative damage of mitochondrial DNA in the gastrocnemius muscle of infected mice. These impairments in mitochondrial-related functions were corroborated by the alteration of key mitochondrial proteins involved in electron transport, mitochondrial biogenesis, dynamics and quality control, and mitochondrial uncoupling. Pharmacological inhibition of MvfR using the potent anti-MvfR lead, D88, we developed, or the mitochondrial-targeted peptide SS-31 rescued the MvfR- mediated alterations observed in mice infected with the wild-type strain PA14. Our study provides insights into the actions of MvfR in orchestrating mitochondrial dysfunction in the skeletal murine muscle, and it presents novel therapeutic approaches for optimizing clinical outcomes in affected patients.

DOI: https://doi.org/10.1101/2024.05.03.592480
Nat Cell Biol. 2024 May;26(5): 674-686

Mitochondrial heterogeneity and adaptations to cellular needs.

Melia Granath-Panelo, Shingo Kajimura.

Although it is well described that mitochondria are at the epicentre of the energy demands of a cell, it is becoming important to consider how each cell tailors its mitochondrial composition and functions to suit its particular needs beyond ATP production. Here we provide insight into mitochondrial heterogeneity throughout development as well as in tissues with specific energy demands and discuss how mitochondrial malleability contributes to cell fate determination and tissue remodelling.

DOI: https://doi.org/10.1038/s41556-024-01410-1
Int J Mol Sci. 2024 Apr 27. pii: 4783. [Epub ahead of print]25(9):

Mitochondria-Derived Vesicles, Sterile Inflammation, and Pyroptosis in Liver Cancer: Partners in Crime or Innocent Bystanders?

Flora Guerra, Francesca Romana Ponziani, Ferdinando Cardone, Cecilia Bucci, Emanuele Marzetti, Anna Picca.

  Alterations in cellular signaling, chronic inflammation, and tissue remodeling contribute to hepatocellular carcinoma (HCC) development. The release of damage-associated molecular patterns (DAMPs) upon tissue injury and the ensuing sterile inflammation have also been attributed a role in HCC pathogenesis. Cargoes of extracellular vesicles (EVs) and/or EVs themselves have been listed among circulating DAMPs but only partially investigated in HCC. Mitochondria-derived vesicles (MDVs), a subpopulation of EVs, are another missing link in the comprehension of the molecular mechanisms underlying the onset and progression of HCC biology. EVs have been involved in HCC growth, dissemination, angiogenesis, and immunosurveillance escape. The contribution of MDVs to these processes is presently unclear. Pyroptosis triggers systemic inflammation through caspase-dependent apoptotic cell death and is implicated in tumor immunity. The analysis of this process, together with MDV characterization, may help capture the relationship among HCC development, mitochondrial quality control, and inflammation. The combination of immune checkpoint inhibitors (i.e., atezolizumab and bevacizumab) has been approved as a synergistic first-line systemic treatment for unresectable or advanced HCC. The lack of biomarkers that may allow prediction of treatment response and, therefore, patient selection, is a major unmet need. Herein, we overview the molecular mechanisms linking mitochondrial dysfunction, inflammation, and pyroptosis, and discuss how immunotherapy targets, at least partly, these routes.

Keywords:  DAMPs; extracellular vesicles; gasdermin; hepatocellular carcinoma; immune checkpoints; immunotherapy; interleukin; miRNAs; mitochondrial-derived vesicles; mtDNA

DOI:  https://doi.org/10.3390/ijms25094783
bioRxiv. 2024 May 05. pii: 2023.04.22.537920. [Epub ahead of print]

ESCRT disruption provides evidence against signaling functions for synaptic exosomes.

Erica C Dresselhaus, Kathryn P Harris, Cassandra R R Blanchette, Kate Koles, Steven J Del Signore, Matthew F Pescosolido, Biljana Ermanoska, Mark Rozencwaig, Rebecca C Soslowsky, Michael J Parisi, Bryan A Stewart, Timothy J Mosca, Avital Adah Rodal.

Extracellular vesicles (EVs) are released by many cell types including neurons, carrying cargoes involved in signaling and disease. It is unclear whether EVs promote intercellular signaling or serve primarily to dispose of unwanted materials. We show that loss of multivesicular endosome-generating ESCRT (endosomal sorting complex required for transport) machinery disrupts release of EV cargoes from Drosophila motor neurons. Surprisingly, ESCRT depletion does not affect the signaling activities of the EV cargo Synaptotagmin-4 (Syt4) and disrupts only some signaling activities of the EV cargo Evenness Interrupted (Evi). Thus, these cargoes may not require intercellular transfer via EVs, and instead may be conventionally secreted or function cell autonomously in the neuron. We find that EVs are phagocytosed by glia and muscles, and that ESCRT disruption causes compensatory autophagy in presynaptic neurons, suggesting that EVs are one of several redundant mechanisms to remove cargoes from synapses. Our results suggest that synaptic EV release serves primarily as a proteostatic mechanism for certain cargoes.

DOI: https://doi.org/10.1101/2023.04.22.537920
Nano Converg. 2024 May 13. 11(1): 19

Extracellular vesicles as nanotheranostic platforms for targeted neurological disorder interventions.

Hye Kyu Choi, Meizi Chen, Li Ling Goldston, Ki-Bum Lee.

  Central Nervous System (CNS) disorders represent a profound public health challenge that affects millions of people around the world. Diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and traumatic brain injury (TBI) exemplify the complexities and diversities that complicate their early detection and the development of effective treatments. Amid these challenges, the emergence of nanotechnology and extracellular vesicles (EVs) signals a new dawn for treating and diagnosing CNS ailments. EVs are cellularly derived lipid bilayer nanosized particles that are pivotal in intercellular communication within the CNS and have the potential to revolutionize targeted therapeutic delivery and the identification of novel biomarkers. Integrating EVs with nanotechnology amplifies their diagnostic and therapeutic capabilities, opening new avenues for managing CNS diseases. This review focuses on examining the fascinating interplay between EVs and nanotechnology in CNS theranostics. Through highlighting the remarkable advancements and unique methodologies, we aim to offer valuable perspectives on how these approaches can bring about a revolutionary change in disease management. The objective is to harness the distinctive attributes of EVs and nanotechnology to forge personalized, efficient interventions for CNS disorders, thereby providing a beacon of hope for affected individuals. In short, the confluence of EVs and nanotechnology heralds a promising frontier for targeted and impactful treatments against CNS diseases, which continue to pose significant public health challenges. By focusing on personalized and powerful diagnostic and therapeutic methods, we might improve the quality of patients.

Keywords:  CNS theranostics; Central nervous system (CNS) diseases; Diagnostic nanotools; EV-based therapeutics; Early diagnosis of neurological disorders; Extracellular vesicles (EVs); Nanotechnology

DOI:  https://doi.org/10.1186/s40580-024-00426-5
J Extracell Vesicles. 2024 May;13(5): e12433

Extracellular vesicles as human therapeutics: A scoping review of the literature.

Clorinda Fusco, Giusy De Rosa, Ilaria Spatocco, Elisabetta Vitiello, Claudio Procaccini, Chiara Frigè, Valeria Pellegrini, Rosalba La Grotta, Roberto Furlan, Giuseppe Matarese, Francesco Prattichizzo, Paola de Candia.

  Extracellular vesicles (EVs) are released by all cells and contribute to cell-to-cell communication. The capacity of EVs to target specific cells and to efficiently deliver a composite profile of functional molecules have led researchers around the world to hypothesize their potential as therapeutics. While studies of EV treatment in animal models are numerous, their actual clinical benefit in humans has more slowly started to be tested. In this scoping review, we searched PubMed and other databases up to 31 December 2023 and, starting from 13,567 records, we selected 40 pertinent published studies testing EVs as therapeutics in humans. The analysis of those 40 studies shows that they are all small pilot trials with a large heterogeneity in terms of administration route and target disease. Moreover, the absence of a placebo control in most of the studies, the predominant local application of EV formulations and the inconsistent administration dose metric still impede comparison across studies and firm conclusions about EV safety and efficacy. On the other hand, the recording of some promising outcomes strongly calls out for well-designed larger studies to test EVs as an alternative approach to treat human diseases with no or few therapeutic options.

Keywords:  clinical trials; exosomes; extracellular vesicles; therapeutics

DOI:  https://doi.org/10.1002/jev2.12433
FASEB J. 2024 May 31. 38(10): e23626

Mechanical stretch preconditioned adipose-derived stem cells elicit polarization of anti-inflammatory M2-like macrophages and improve chronic wound healing.

Jiahao He, Shengzhou Shan, Taoran Jiang, Sizheng Zhou, Jiaqi Qin, Qingfeng Li, Zheyuan Yu, Dejun Cao, Bin Fang.

  Transplantation of adipose-derived stem cells (ASCs) is a promising option in the field of chronic wounds treatment. However, the effectiveness of ASCs therapies has been hampered by highly inflammatory environment in chronic wound areas. These problems could be partially circumvented using efficient approaches that boost the survival and anti-inflammatory capacity of transplanted ASCs. Here, by application of mechanical stretch (MS), we show that ASCs exhibits increased survival and immunoregulatory properties in vitro. MS triggers the secretion of macrophage colony stimulating factor (M-CSF) from ASCs, a chemokine that is linked to anti-inflammatory M2-like macrophages polarization. When the MS-ASCs were transplanted to chronic wounds, the wound area yields significantly faster closure rate and lower inflammatory mediators, largely due to macrophages polarization driven by transplanted MS-ASCs. Thus, our work shows that mechanical stretch can be harnessed to enhance ASCs transplantation efficiency in chronic wounds treatment.

Keywords:  adipose‐derived stem cells; anti‐inflammatory M2‐like macrophages; chronic wounds; mechanical stretch

DOI:  https://doi.org/10.1096/fj.202300586R
Psychiatry Res. 2024 May 08. pii: S0165-1781(24)00239-7. [Epub ahead of print]337 115954

The emerging role of extracellular vesicles in the diagnosis and treatment of autism spectrum disorders.

Xue Lei, Xue-Ni Xie, Jia-Xin Yang, Ya-Min Li.

  Autism spectrum disorders (ASD) are neurodevelopmental conditions characterized by restricted, repetitive behavioral patterns and deficits in social interactions. The prevalence of ASD has continued to rise in recent years. However, the etiology and pathophysiology of ASD remain largely unknown. Currently, the diagnosis of ASD relies on behavior measures, and there is a lack of reliable and objective biomarkers. In addition, there are still no effective pharmacologic therapies for the core symptoms of ASD. Extracellular vesicles (EVs) are lipid bilayer nanovesicles secreted by almost all types of cells. EVs play a vital role in cell-cell communications and are known to bear various biological functions. Emerging evidence demonstrated that EVs are involved in many physiological and pathological processes throughout the body and the content in EVs can reflect the status of the originating cells. EVs have demonstrated the potential of broad applications for the diagnosis and treatment of various brain diseases, suggesting that EVs may have also played a role in the pathological process of ASD. Besides, EVs can be utilized as therapeutic agents for their endogenous substances and biological functions. Additionally, EVs can serve as drug delivery tools as nano-sized vesicles with inherent targeting ability. Here, we discuss the potential of EVs to be considered as promising diagnostic biomarkers and their potential therapeutic applications for ASD.

Keywords:  Autism spectrum disorders; Biomarkers; Diagnosis; Extracellular vesicles; Therapy

DOI:  https://doi.org/10.1016/j.psychres.2024.115954
Nat Rev Gastroenterol Hepatol. 2024 May 13.

Mitochondrial function and gastrointestinal diseases.

Parsa S Haque, Neeraj Kapur, Terrence A Barrett, Arianne L Theiss.

Mitochondria are dynamic organelles that function in cellular energy metabolism, intracellular and extracellular signalling, cellular fate and stress responses. Mitochondria of the intestinal epithelium, the cellular interface between self and enteric microbiota, have emerged as crucial in intestinal health. Mitochondrial dysfunction occurs in gastrointestinal diseases, including inflammatory bowel diseases and colorectal cancer. In this Review, we provide an overview of the current understanding of intestinal epithelial cell mitochondrial metabolism, function and signalling to affect tissue homeostasis, including gut microbiota composition. We also discuss mitochondrial-targeted therapeutics for inflammatory bowel diseases and colorectal cancer and the evolving concept of mitochondrial impairment as a consequence versus initiator of the disease.

DOI: https://doi.org/10.1038/s41575-024-00931-2
J Nanobiotechnology. 2024 May 16. 22(1): 255

Extracellular vesicles from senescent mesenchymal stromal cells are defective and cannot prevent osteoarthritis.

Boulestreau Jérémy, Maumus Marie, Bertolino M Giuliana, Toupet Karine, Jorgensen Christian, Noël Danièle.

  Age is the most important risk factor in degenerative diseases such as osteoarthritis (OA), which is associated with the accumulation of senescent cells in the joints. Here, we aimed to assess the impact of senescence on the therapeutic properties of extracellular vesicles (EVs) from human fat mesenchymal stromal cells (ASCs) in OA. We generated a model of DNA damage-induced senescence in ASCs using etoposide and characterized EVs isolated from their conditioned medium (CM). Senescent ASCs (S-ASCs) produced 3-fold more EVs (S-EVs) with a slightly bigger size and that contain 2-fold less total RNA. Coculture experiments showed that S-ASCs were as efficient as healthy ASCs (H-ASCs) in improving the phenotype of OA chondrocytes cultured in resting conditions but were defective when chondrocytes were proliferating. S-EVs were also impaired in their capacity to polarize synovial macrophages towards an anti-inflammatory phenotype. A differential protein cargo mainly related to inflammation and senescence was detected in S-EVs and H-EVs. Using the collagenase-induced OA model, we found that contrary to H-EVs, S-EVs could not protect mice from cartilage damage and joint calcifications, and were less efficient in protecting subchondral bone degradation. In addition, S-EVs induced a pro-catabolic and pro-inflammatory gene signature in the joints of mice shortly after injection, while H-EVs decreased hypertrophic, catabolic and inflammatory pathways. In conclusion, S-EVs are functionally impaired and cannot protect mice from developing OA.

Keywords:  Aging; Extracellular vesicle; Mesenchymal stromal cell; Osteoarthritis; Regenerative medicine; Senescence

DOI:  https://doi.org/10.1186/s12951-024-02509-1
PLoS One. 2024 ;19(5): e0300787

Muscle Psn gene combined with exercise contribute to healthy aging of skeletal muscle and lifespan by adaptively regulating Sirt1/PGC-1α and arm pathway.

Ying-Hui Gao, Deng-Tai Wen, Zhong-Rui Du, Jing-Feng Wang, Shi-Jie Wang.

The Presenilin (Psn) gene is closely related to aging, but it is still unclear the role of Psn genes in skeletal muscle. Here, the Psn-UAS/Mhc-GAL4 system in Drosophila was used to regulate muscle Psn overexpression(MPO) and muscle Psn knockdown(MPK). Drosophila were subjected to endurance exercise from 4 weeks to 5 weeks old. The results showed that MPO and exercise significantly increased climbing speed, climbing endurance, lifespan, muscle SOD activity, Psn expression, Sirt1 expression, PGC-1α expression, and armadillo (arm) expression in aged Drosophila, and they significantly decreased muscle malondialdehyde levels. Interestingly, when the Psn gene is knockdown by 0.78 times, the PGC-1α expression and arm expression were also down-regulated, but the exercise capacity and lifespan were increased. Furthermore, exercise combined with MPO further improved the exercise capacity and lifespan. MPK combined with exercise further improves the exercise capacity and lifespan. Thus, current results confirmed that the muscle Psn gene was a vital gene that contributed to the healthy aging of skeletal muscle since whether it was overexpressed or knocked down, the aging progress of skeletal muscle structure and function was slowed down by regulating the activity homeostasis of Sirt1/PGC-1α pathway and Psn/arm pathway. Exercise enhanced the function of the Psn gene to delay skeletal muscle aging by up regulating the activity of the Sirt1/PGC-1α pathway and Psn/arm pathway.

DOI: https://doi.org/10.1371/journal.pone.0300787
Invertebr Syst. 2024 May;pii: IS24029. [Epub ahead of print]38

Mitogenome architecture supports the non-monophyly of the cosmopolitan parasitoid wasp subfamily Doryctinae (Hymenoptera: Braconidae) recovered by nuclear and mitochondrial phylogenomics.

Rubén Castañeda-Osorio, Sergey A Belokobylskij, Jovana M Jasso-Martínez, Ernesto Samacá-Sáenz, Robert R Kula, Alejandro Zaldívar-Riverón.

Mitochondrial DNA gene organisation is an important source of phylogenetic information for various metazoan taxa at different evolutionary timescales, though this has not been broadly tested for all insect groups nor within a phylogenetic context. The cosmopolitan subfamily Doryctinae is a highly diverse group of braconid wasps mainly represented by ectoparasitoids of xylophagous beetle larvae. Previous molecular studies based on Sanger and genome-wide (ultraconserved elements, UCE; and mitochondrial genomes) sequence data have recovered a non-monophyletic Doryctinae, though the relationships involved have always been weakly supported. We characterised doryctine mitogenomes and conducted separate phylogenetic analyses based on mitogenome and UCE sequence data of ~100 representative doryctine genera to assess the monophyly and higher-level classification of the subfamily. We identified rearrangements of mitochondrial transfer RNAs (tRNAs) that support a non-monophyletic Doryctinae consisting of two separate non-related clades with strong geographic structure ('New World' and 'Old World' clades). This geographic structure was also consistently supported by the phylogenetic analyses preformed with mitogenome and UCE sequence data. These results highlight the utility of the mitogenome gene rearrangements as a potential source of phylogenetic information at different evolutionary timescales.

DOI: https://doi.org/10.1071/IS24029
Res Sq. 2024 May 02. pii: rs.3.rs-4284907. [Epub ahead of print]

Regulation of Vascular Endothelial Integrity by Mesenchymal Stem Cell Extracellular Vesicles after Hemorrhagic Shock and Trauma.

Mark Barry, Alpa Trivedi, Byron Miyazawa, Lindsay Vivona, David Shimmin, Praneeti Pathipati, Callie Keane, Joseph Cuschieri, Shibani Pati.

BACKGROUND Patients with hemorrhagic shock and trauma (HS/T) are vulnerable to the endotheliopathy of trauma (EOT), characterized by vascular barrier dysfunction, inflammation, and coagulopathy. Cellular therapies such as mesenchymal stem cells (MSCs) and MSC extracellular vesicles (EVs) have been proposed as potential therapies targeting the EOT. In this study we investigated the effects of MSCs and MSC EVs on endothelial and epithelial barrier integrity in vitro and in vivo in a mouse model of HS/T. This study addresses systemic effects of HS/T on multiorgan EOT in HS/T model. METHODS In vitro , pulmonary endothelial cell (PEC) and Caco-2 intestinal epithelial cell monolayers were treated with control media, MSC conditioned media (CM), or MSC EVs in varying doses and subjected to a thrombin or hydrogen peroxide (H 2 O 2 ) challenge, respectively. Monolayer permeability was evaluated with a cell impedance assay, and intercellular junction integrity was evaluated with immunofluorescent staining. In vivo , a mouse model of HS/T was used to evaluate the effects of lactated Ringer's (LR), MSCs, and MSC EVs on endothelial and epithelial intercellular junctions in the lung and small intestine as well as on plasma inflammatory biomarkers. RESULTS MSC EVs and MSC CM attenuated permeability and preserved intercellular junctions of the PEC monolayer in vitro, whereas only MSC CM was protective of the Caco-2 epithelial monolayer. In vivo , both MSC EVs and MSCs mitigated the loss of endothelial adherens junctions in the lung and small intestine, though only MSCs had a protective effect on epithelial tight junctions in the lung. Several plasma biomarkers including MMP8 and VEGF were elevated in LR- and EV-treated but not MSC-treated mice. CONCLUSIONS In conclusion, MSC EVs could be a potential cell-free therapy targeting endotheliopathy after HS/T via preservation of the vascular endothelial barrier in multiple organs early after injury. Further research is needed to better understand the immunomodulatory effects of these products following HS/T and to move toward translating these therapies into clinical studies.

DOI: https://doi.org/10.21203/rs.3.rs-4284907/v1
bioRxiv. 2024 May 02. pii: 2024.04.29.589900. [Epub ahead of print]

Rapid Assessment of Biomarkers on Single Extracellular Vesicles Using 'Catch and Display' on Ultrathin Nanoporous Silicon Nitride Membranes.

Samuel N Walker, Kilean Lucas, Marley J Dewey, Stephen Badylak, George Hussey, Jonathan Flax, James L McGrath.

Extracellular vesicles (EVs) are particles secreted by all cells that carry bioactive cargo and facilitate intercellular communication with roles in normal physiology and disease pathogenesis. EVs have tremendous diagnostic and therapeutic potential and accordingly, the EV field has grown exponentially in recent years. Bulk assays lack the sensitivity to detect rare EV subsets relevant to disease, and while single EV analysis techniques remedy this, they are undermined by complicated detection schemes often coupled with prohibitive instrumentation. To address these issues, we propose a microfluidic technique for EV characterization called ' ca tch and d isplay for l iquid b iopsy (CAD-LB)'. CAD-LB rapidly captures fluorescently labeled EVs in the similarly-sized pores of an ultrathin silicon nitride membrane. Minimally processed sample is introduced via pipette injection into a simple microfluidic device which is directly imaged using fluorescence microscopy for a rapid assessment of EV number and biomarker colocalization. In this work, nanoparticles were first used to define the accuracy and dynamic range for counting and colocalization by CAD-LB. Following this, the same assessments were made for purified EVs and for unpurified EVs in plasma. Biomarker detection was validated using CD9 in which Western blot analysis confirmed that CAD-LB faithfully recapitulated differing expression levels among samples. We further verified that CAD-LB captured the known increase in EV-associated ICAM-1 following the cytokine stimulation of endothelial cells. Finally, to demonstrate CAD-LB's clinical potential, we show that EV biomarkers indicative of immunotherapy responsiveness are successfully detected in the plasma of bladder cancer patients undergoing immune checkpoint blockade.

DOI: https://doi.org/10.1101/2024.04.29.589900
Aging Dis. 2024 Apr 25.

The Role of Protein S-Nitrosylation in Mitochondrial Quality Control in Central Nervous System Diseases.

Fang Qiu, Yuqiang Liu, Zhiheng Liu.

S-Nitrosylation is a reversible covalent post-translational modification. Under physiological conditions, S-nitrosylation plays a dynamic role in a wide range of biological processes by regulating the function of substrate proteins. Like other post-translational modifications, S-nitrosylation can affect protein conformation, activity, localization, aggregation, and protein interactions. Aberrant S-nitrosylation can lead to protein misfolding, mitochondrial fragmentation, synaptic damage, and autophagy. Mitochondria are essential organelles in energy production, metabolite biosynthesis, cell death, and immune responses, among other processes. Mitochondrial dysfunction can result in cell death and has been implicated in the development of many human diseases. Recent evidence suggests that S-nitrosylation and mitochondrial dysfunction are important modulators of the progression of several diseases. In this review, we highlight recent findings regarding the aberrant S- nitrosylation of mitochondrial proteins that regulate mitochondrial biosynthesis, fission and fusion, and autophagy. Specifically, we discuss the mechanisms by which S-nitrosylated mitochondrial proteins exercise mitochondrial quality control under pathological conditions, thereby influencing disease. A better understanding of these pathological events may provide novel therapeutic targets to mitigate the development of neurological diseases.

DOI: https://doi.org/10.14336/AD.2024.0099
Cell Commun Signal. 2024 May 16. 22(1): 273

Integrated proteomic, phosphoproteomic, and N-glycoproteomic analyses of small extracellular vesicles from C2C12 myoblasts identify specific PTM patterns in ligand-receptor interactions.

Xiulan Chen, Xi Song, Jiaran Li, Jifeng Wang, Yumeng Yan, Fuquan Yang.

  Small extracellular vesicles (sEVs) are important mediators of intercellular communication by transferring of functional components (proteins, RNAs, and lipids) to recipient cells. Some PTMs, including phosphorylation and N-glycosylation, have been reported to play important role in EV biology, such as biogenesis, protein sorting and uptake of sEVs. MS-based proteomic technology has been applied to identify proteins and PTM modifications in sEVs. Previous proteomic studies of sEVs from C2C12 myoblasts, an important skeletal muscle cell line, focused on identification of proteins, but no PTM information on sEVs proteins is available.In this study, we systematically analyzed the proteome, phosphoproteome, and N-glycoproteome of sEVs from C2C12 myoblasts with LC-MS/MS. In-depth analyses of the three proteomic datasets revealed that the three proteomes identified different catalogues of proteins, and PTMomic analysis could expand the identification of cargos in sEVs. At the proteomic level, a high percentage of membrane proteins, especially tetraspanins, was identified. The sEVs-derived phosphoproteome had a remarkably high level of tyrosine-phosphorylated sites. The tyrosine-phosphorylated proteins might be involved with EPH-Ephrin signaling pathway. At the level of N-glycoproteomics, several glycoforms, such as complex N-linked glycans and sialic acids on glycans, were enriched in sEVs. Retrieving of the ligand-receptor interaction in sEVs revealed that extracellular matrix (ECM) and cell adhesion molecule (CAM) represented the most abundant ligand-receptor pairs in sEVs. Mapping the PTM information on the ligands and receptors revealed that N-glycosylation mainly occurred on ECM and CAM proteins, while phosphorylation occurred on different categories of receptors and ligands. A comprehensive PTM map of ECM-receptor interaction and their components is also provided.In summary, we conducted a comprehensive proteomic and PTMomic analysis of sEVs of C2C12 myoblasts. Integrated proteomic, phosphoproteomic, and N-glycoproteomic analysis of sEVs might provide some insights about their specific uptake mechanism.

Keywords:   N-glycoproteomics; C2C12 myoblast; LC–MS/MS; Ligand-receptor interaction; Membrane transporters; Phosphoproteomics; Proteomics; Skeletal muscle; Small extracellular vesicles (sEVs)

DOI:  https://doi.org/10.1186/s12964-024-01640-8
Cell Mol Immunol. 2024 May 14.

Neutrophil-macrophage communication via extracellular vesicle transfer promotes itaconate accumulation and ameliorates cytokine storm syndrome.

Haixia Kang, Ting Liu, Yuanyuan Wang, Wenjuan Bai, Yan Luo, Jing Wang.

  Cytokine storm syndrome (CSS) is a life-threatening systemic inflammatory syndrome involving innate immune hyperactivity triggered by various therapies, infections, and autoimmune conditions. However, the potential interplay between innate immune cells is not fully understood. Here, using poly I:C and lipopolysaccharide (LPS)-induced cytokine storm models, a protective role of neutrophils through the modulation of macrophage activation was identified in a CSS model. Intravital imaging revealed neutrophil-derived extracellular vesicles (NDEVs) in the liver and spleen, which were captured by macrophages. NDEVs suppressed proinflammatory cytokine production by macrophages when cocultured in vitro or infused into CSS models. Metabolic profiling of macrophages treated with NDEV revealed elevated levels of the anti-inflammatory metabolite, itaconate, which is produced from cis-aconitate in the Krebs cycle by cis-aconitate decarboxylase (Acod1, encoded by Irg1). Irg1 in macrophages, but not in neutrophils, was critical for the NDEV-mediated anti-inflammatory effects. Mechanistically, NDEVs delivered miR-27a-3p, which suppressed the expression of Suclg1, the gene encoding the enzyme that metabolizes itaconate, thereby resulting in the accumulation of itaconate in macrophages. These findings demonstrated that neutrophil-to-macrophage communication mediated by extracellular vesicles is critical for promoting the anti-inflammatory reprogramming of macrophages in CSS and may have potential implications for the treatment of this fatal condition.

Keywords:  Cytokine storm syndrome; Extracellular vesicle; Itaconate; Macrophage; Neutrophil

DOI:  https://doi.org/10.1038/s41423-024-01174-6