bims-mitrat Biomed News
on Mitochondrial transplantation and transfer
Issue of 2024–07–07
fifteen papers selected by
Gökhan Burçin Kubat, Gulhane Health Sciences Institute
  1. The importance of platelet-derived mitochondrial transplantation in ischemic heart disease: A clinical study.
  2. Neuroprotective effect of autologous mitochondrial transplantation against global ischemia/reperfusion injury in a rat model of cardiac arrest.
  3. Beyond fission and fusion-Diving into the mysteries of mitochondrial shape.
  4. Protocol for detecting mitochondria extracellular vesicles of brown adipose tissue in mice.
  5. Overexpression of mitochondrial fission or mitochondrial fusion genes enhances resilience and extends longevity.
  6. Exosomes: compositions, biogenesis, and mechanisms in diabetic wound healing.
  7. Mitochondrial Thermogenesis Can Trigger Heat Shock Response in the Nucleus.
  8. Mitochondrial unfolded protein response mechanism and its cardiovascular protective effects.
  9. Enhancing extracellular vesicle cargo loading and functional delivery by engineering protein-lipid interactions.
  10. Trafficking of mitochondrial double-stranded RNA from mitochondria to the cytosol.
  11. Preventing loss of sirt1 lowers mitochondrial oxidative stress and preserves C2C12 myotube diameter in an in vitro model of cancer cachexia.
  12. Proteomic profiling of mesenchymal stem cell-derived extracellular vesicles: Impact of isolation methods on protein cargo.
  13. Mitochondrial genetics through the lens of single-cell multi-omics.
  14. mitoPADdb: A database of mitochondrial proteins associated with diseases.
  15. A systematic review and meta-analysis of clinical trials assessing safety and efficacy of human extracellular vesicle-based therapy.
  1. Int J Cardiol. 2024 Jun 29. pii: S0167-5273(24)00934-3. [Epub ahead of print]412 132312
    The importance of platelet-derived mitochondrial transplantation in ischemic heart disease: A clinical study.
    Gokhan Burcin Kubat.
      
    DOI:  https://doi.org/10.1016/j.ijcard.2024.132312
  2. Mitochondrion. 2024 Jun 27. pii: S1567-7249(24)00082-5. [Epub ahead of print]78 101924
    Neuroprotective effect of autologous mitochondrial transplantation against global ischemia/reperfusion injury in a rat model of cardiac arrest.
    MengDa Xu, Jie Zhu, Zhen Wang, JingYu Yan, Xiang Zhou.
       BACKGROUND: Mitochondria have emerged as a promising target for ischemic disease. A previous study reported the application of mitochondrial transplantation in focal cerebral ischemia/reperfusion injury, but it is unclear whether exogenous mitochondrial transplantation could be a therapeutic strategy for global ischemia/reperfusion injury induced by cardiac arrest.
    METHODS: We hypothesized that transplantation of autologous mitochondria would rescue hippocampal cells and alleviate neurological impairment after cardiac arrest. In this study, we employed a rat cardiac arrest-global cerebral ischemia injury model (CA-GCII) and transplanted isolated mitochondria intravenously. Behavior test was applied to assess neurological deficit. Apoptosis and mitochondria permeability transition pore opening in hippocampus was determined using immunoblotting and swelling assay, respectively.
    RESULTS: Transplanted mitochondria distributed throughout hippocampal cells and reduced oxidative stress. An improved neurological outcome was observed in rats receiving autologous mitochondria. In the hippocampus, mitophagy was enhanced while cell apoptosis was induced by ischemia/reperfusion insult was downregulated by mitochondrial transplantation. Mitochondrial permeability transition pore (MPTP) opening in surviving hippocampal cells was also suppressed.
    CONCLUSIONS: These results indicated that transplantation of autologous mitochondria rescued hippocampal cells from ischemia/reperfusion injury and ameliorated neurological impairment caused by cardiac arrest.
    Keywords:  Apoptosis; Cardiac arrest; Global cerebral ischemia/reperfusion injury; Mitochondrial permeability transition pore; Mitochondrial transplantation
    DOI:  https://doi.org/10.1016/j.mito.2024.101924
  3. PLoS Biol. 2024 Jul;22(7): e3002671
    Beyond fission and fusion-Diving into the mysteries of mitochondrial shape.
    Noga Preminger, Maya Schuldiner.
      Mitochondrial shape and network formation have been primarily associated with the well-established processes of fission and fusion. However, recent research has unveiled an intricate and multifaceted landscape of mitochondrial morphology that extends far beyond the conventional fission-fusion paradigm. These less-explored dimensions harbor numerous unresolved mysteries. This review navigates through diverse processes influencing mitochondrial shape and network formation, highlighting the intriguing complexities and gaps in our understanding of mitochondrial architecture. The exploration encompasses various scales, from biophysical principles governing membrane dynamics to molecular machineries shaping mitochondria, presenting a roadmap for future research in this evolving field.
    DOI:  https://doi.org/10.1371/journal.pbio.3002671
  4. STAR Protoc. 2024 Jun 27. pii: S2666-1667(24)00326-5. [Epub ahead of print]5(3): 103161
    Protocol for detecting mitochondria extracellular vesicles of brown adipose tissue in mice.
    Flavia Tortolici, Claudia Di Biagio, Daniele Lettieri-Barbato, Katia Aquilano.
      Brown adipose tissue (BAT) is mitochondria rich, enabling high oxidative metabolism for non-shivering thermogenesis. The release of large/small extracellular vesicles (EVs) containing mitochondria or mitochondrial fragments, termed mito-EVs, may support mitochondrial quality control or intercellular communication. We present a protocol to isolate and characterize mito-EVs. We detail steps for BAT processing, cell debris removal, differential centrifugation (dC), and mito-EV analysis by flow cytometry and immunoblotting assays. For complete details on the use and execution of this protocol, please refer to Rosina et al.1.
    Keywords:  Cell Biology; Cell Membrane; Cell culture; Flow Cytometry; Metabolism; Molecular Biology; Protein Biochemistry
    DOI:  https://doi.org/10.1016/j.xpro.2024.103161
  5. Aging Cell. 2024 Jul 02. e14262
    Overexpression of mitochondrial fission or mitochondrial fusion genes enhances resilience and extends longevity.
    Annika Traa, Allison Keil, Abdelrahman AlOkda, Suleima Jacob-Tomas, Aura A Tamez González, Shusen Zhu, Zenith Rudich, Jeremy M Van Raamsdonk.
      The dynamicity of the mitochondrial network is crucial for meeting the ever-changing metabolic and energy needs of the cell. Mitochondrial fission promotes the degradation and distribution of mitochondria, while mitochondrial fusion maintains mitochondrial function through the complementation of mitochondrial components. Previously, we have reported that mitochondrial networks are tubular, interconnected, and well-organized in young, healthy C. elegans, but become fragmented and disorganized with advancing age and in models of age-associated neurodegenerative disease. In this work, we examine the effects of increasing mitochondrial fission or mitochondrial fusion capacity by ubiquitously overexpressing the mitochondrial fission gene drp-1 or the mitochondrial fusion genes fzo-1 and eat-3, individually or in combination. We then measured mitochondrial function, mitochondrial network morphology, physiologic rates, stress resistance, and lifespan. Surprisingly, we found that overexpression of either mitochondrial fission or fusion machinery both resulted in an increase in mitochondrial fragmentation. Similarly, both mitochondrial fission and mitochondrial fusion overexpression strains have extended lifespans and increased stress resistance, which in the case of the mitochondrial fusion overexpression strains appears to be at least partially due to the upregulation of multiple pathways of cellular resilience in these strains. Overall, our work demonstrates that increasing the expression of mitochondrial fission or fusion genes extends lifespan and improves biological resilience without promoting the maintenance of a youthful mitochondrial network morphology. This work highlights the importance of the mitochondria for both resilience and longevity.
    Keywords:   C. elegans ; aging; biological resilience; genetics; lifespan; mitochondria; mitochondrial fission; mitochondrial fusion
    DOI:  https://doi.org/10.1111/acel.14262
  6. J Nanobiotechnology. 2024 Jul 05. 22(1): 398
    Exosomes: compositions, biogenesis, and mechanisms in diabetic wound healing.
    Yichuan Li, Zhanyong Zhu, Sicheng Li, Xiaohang Xie, Lei Qin, Qi Zhang, Yan Yang, Ting Wang, Yong Zhang.
      Diabetic wounds are characterized by incomplete healing and delayed healing, resulting in a considerable global health care burden. Exosomes are lipid bilayer structures secreted by nearly all cells and express characteristic conserved proteins and parent cell-associated proteins. Exosomes harbor a diverse range of biologically active macromolecules and small molecules that can act as messengers between different cells, triggering functional changes in recipient cells and thus endowing the ability to cure various diseases, including diabetic wounds. Exosomes accelerate diabetic wound healing by regulating cellular function, inhibiting oxidative stress damage, suppressing the inflammatory response, promoting vascular regeneration, accelerating epithelial regeneration, facilitating collagen remodeling, and reducing scarring. Exosomes from different tissues or cells potentially possess functions of varying levels and can promote wound healing. For example, mesenchymal stem cell-derived exosomes (MSC-exos) have favorable potential in the field of healing due to their superior stability, permeability, biocompatibility, and immunomodulatory properties. Exosomes, which are derived from skin cellular components, can modulate inflammation and promote the regeneration of key skin cells, which in turn promotes skin healing. Therefore, this review mainly emphasizes the roles and mechanisms of exosomes from different sources, represented by MSCs and skin sources, in improving diabetic wound healing. A deeper understanding of therapeutic exosomes will yield promising candidates and perspectives for diabetic wound healing management.
    Keywords:  Diabetes; Exosomes; Immune regulation; MSCs; Regeneration; ncRNAs
    DOI:  https://doi.org/10.1186/s12951-024-02684-1
  7. ACS Cent Sci. 2024 Jun 26. 10(6): 1231-1241
    Mitochondrial Thermogenesis Can Trigger Heat Shock Response in the Nucleus.
    Myeong-Gyun Kang, Hwa-Ryeon Kim, Hee Yong Lee, Chulhwan Kwak, Hyewon Koh, Byoung Heon Kang, Jae-Seok Roe, Hyun-Woo Rhee.
      Mitochondrial thermogenesis is a process in which heat is generated by mitochondrial respiration. In living organisms, the thermogenic mechanisms that maintain body temperature have been studied extensively in fat cells with little knowledge on how mitochondrial heat may act beyond energy expenditure. Here, we highlight that the exothermic oxygen reduction reaction (ΔH f° = -286 kJ/mol) is the main source of the protonophore-induced mitochondrial thermogenesis, and this heat is conducted to other cellular organelles, including the nucleus. As a result, mitochondrial heat that reached the nucleus initiated the classical heat shock response, including the formation of nuclear stress granules and the localization of heat shock factor 1 (HSF1) to chromatin. Consequently, activated HSF1 increases the level of gene expression associated with the response to thermal stress in mammalian cells. Our results illustrate heat generated within the cells as a potential source of mitochondria-nucleus communication and expand our understanding of the biological functions of mitochondria in cell physiology.
    DOI:  https://doi.org/10.1021/acscentsci.3c01589
  8. Biomed Pharmacother. 2024 Jul 02. pii: S0753-3322(24)00873-4. [Epub ahead of print]177 116989
    Mitochondrial unfolded protein response mechanism and its cardiovascular protective effects.
    Jinlan Deng, Danyang Wang, Yanmei Shi, Lin Lin, Weihan Gao, Yu Sun, Xiayinan Song, Yunlun Li, Jie Li.
      The mitochondrial unfolded protein response (UPRmt) is a cytoprotective response in response to cellular stress that is activated in response to mitochondrial stress to maintain intra-protein homeostasis, thereby protecting the cell from a variety of stimuli. The activation of this response has been linked to cardiovascular diseases. Here, we reviewed the current understanding of UPRmt and discussed its specific molecular mechanism, mainly in mammals, as well as addressing its protective role against cardiovascular diseases, so as to provide direction for further research on UPRmt and therapies targeting cardiovascular diseases in the future.
    Keywords:  Cardiovascular diseases; Factors; Molecular mechanism; UPR(mt)
    DOI:  https://doi.org/10.1016/j.biopha.2024.116989
  9. Nat Commun. 2024 Jul 04. 15(1): 5618
    Enhancing extracellular vesicle cargo loading and functional delivery by engineering protein-lipid interactions.
    Justin A Peruzzi, Taylor F Gunnels, Hailey I Edelstein, Peilong Lu, David Baker, Joshua N Leonard, Neha P Kamat.
      Naturally generated lipid nanoparticles termed extracellular vesicles (EVs) hold significant promise as engineerable therapeutic delivery vehicles. However, active loading of protein cargo into EVs in a manner that is useful for delivery remains a challenge. Here, we demonstrate that by rationally designing proteins to traffic to the plasma membrane and associate with lipid rafts, we can enhance loading of protein cargo into EVs for a set of structurally diverse transmembrane and peripheral membrane proteins. We then demonstrate the capacity of select lipid tags to mediate increased EV loading and functional delivery of an engineered transcription factor to modulate gene expression in target cells. We envision that this technology could be leveraged to develop new EV-based therapeutics that deliver a wide array of macromolecular cargo.
    DOI:  https://doi.org/10.1038/s41467-024-49678-z
  10. Life Sci Alliance. 2024 Sep;pii: e202302396. [Epub ahead of print]7(9):
    Trafficking of mitochondrial double-stranded RNA from mitochondria to the cytosol.
    Matthew R Krieger, Melania Abrahamian, Kevin L He, Sean Atamdede, Hesamedin Hakimjavadi, Milica Momcilovic, Dejerianne Ostrow, Simran Ds Maggo, Yik Pui Tsang, Xiaowu Gai, Guillaume F Chanfreau, David B Shackelford, Michael A Teitell, Carla M Koehler.
      In addition to mitochondrial DNA, mitochondrial double-stranded RNA (mtdsRNA) is exported from mitochondria. However, specific channels for RNA transport have not been demonstrated. Here, we begin to characterize channel candidates for mtdsRNA export from the mitochondrial matrix to the cytosol. Down-regulation of SUV3 resulted in the accumulation of mtdsRNAs in the matrix, whereas down-regulation of PNPase resulted in the export of mtdsRNAs to the cytosol. Targeting experiments show that PNPase functions in both the intermembrane space and matrix. Strand-specific sequencing of the double-stranded RNA confirms the mitochondrial origin. Inhibiting or down-regulating outer membrane proteins VDAC1/2 and BAK/BAX or inner membrane proteins PHB1/2 strongly attenuated the export of mtdsRNAs to the cytosol. The cytosolic mtdsRNAs subsequently localized to large granules containing the stress protein TIA-1 and activated the type 1 interferon stress response pathway. Abundant mtdsRNAs were detected in a subset of non-small-cell lung cancer cell lines that were glycolytic, indicating relevance in cancer biology. Thus, we propose that mtdsRNA is a new damage-associated molecular pattern that is exported from mitochondria in a regulated manner.
    DOI:  https://doi.org/10.26508/lsa.202302396
  11. Physiol Rep. 2024 Jul;12(13): e16103
    Preventing loss of sirt1 lowers mitochondrial oxidative stress and preserves C2C12 myotube diameter in an in vitro model of cancer cachexia.
    Brian A Hain, Scot R Kimball, David L Waning.
      Cancer cachexia is a multifactorial syndrome associated with advanced cancer that contributes to mortality. Cachexia is characterized by loss of body weight and muscle atrophy. Increased skeletal muscle mitochondrial reactive oxygen species (ROS) is a contributing factor to loss of muscle mass in cachectic patients. Mice inoculated with Lewis lung carcinoma (LLC) cells lose weight, muscle mass, and have lower muscle sirtuin-1 (sirt1) expression. Nicotinic acid (NA) is a precursor to nicotinamide dinucleotide (NAD+) which is exhausted in cachectic muscle and is a direct activator of sirt1. Mice lost body and muscle weight and exhibited reduced skeletal muscle sirt1 expression after inoculation with LLC cells. C2C12 myotubes treated with LLC-conditioned media (LCM) had lower myotube diameter. We treated C2C12 myotubes with LCM for 24 h with or without NA for 24 h. C2C12 myotubes treated with NA maintained myotube diameter, sirt1 expression, and had lower mitochondrial superoxide. We then used a sirt1-specific small molecule activator SRT1720 to increase sirt1 activity. C2C12 myotubes treated with SRT1720 maintained myotube diameter, prevented loss of sirt1 expression, and attenuated mitochondrial superoxide production. Our data provides evidence that NA may be beneficial in combating cancer cachexia by maintaining sirt1 expression and decreasing mitochondrial superoxide production.
    Keywords:  cancer cachexia; mitochondria; nicotinic acid; oxidative stress; sirtuin‐1
    DOI:  https://doi.org/10.14814/phy2.16103
  12. J Extracell Biol. 2024 Jun;3(6): e159
    Proteomic profiling of mesenchymal stem cell-derived extracellular vesicles: Impact of isolation methods on protein cargo.
    Morteza Abyadeh, Shahab Mirshahvaladi, Sara Assar Kashani, Joao A Paulo, Ardeshir Amirkhani, Fatemeh Mehryab, Homeyra Seydi, Niloufar Moradpour, Sheyda Jodeiryjabarzade, Mehdi Mirzaei, Vivek Gupta, Faezeh Shekari, Ghasem Hosseini Salekdeh.
      Extracellular vesicles (EVs) are nanosized vesicles with a lipid bilayer that are secreted by cells and play a critical role in cell-to-cell communication. Despite the promising reports regarding their diagnostic and therapeutic potential, the utilization of EVs in the clinical setting is limited due to insufficient information about their cargo and a lack of standardization in isolation and analysis methods. Considering protein cargos in EVs as key contributors to their therapeutic potency, we conducted a tandem mass tag (TMT) quantitative proteomics analysis of three subpopulations of mesenchymal stem cell (MSC)-derived EVs obtained through three different isolation techniques: ultracentrifugation (UC), high-speed centrifugation (HS), and ultracentrifugation on sucrose cushion (SU). Subsequently, we checked EV marker expression, size distribution, and morphological characterization, followed by bioinformatic analysis. The bioinformatic analysis of the proteome results revealed that these subpopulations exhibit distinct molecular and functional characteristics. The choice of isolation method impacts the proteome of isolated EVs by isolating different subpopulations of EVs. Specifically, EVs isolated through the high-speed centrifugation (HS) method exhibited a higher abundance of ribosomal and mitochondrial proteins. Functional apoptosis assays comparing isolated mitochondria with EVs isolated through different methods revealed that HS-EVs, but not other EVs, induced early apoptosis in cancer cells. On the other hand, EVs isolated using the sucrose cushion (SU) and ultracentrifugation (UC) methods demonstrated a higher abundance of proteins primarily involved in the immune response, cell-cell interactions and extracellular matrix interactions. Our analyses unveil notable disparities in proteins and associated biological functions among EV subpopulations, underscoring the importance of meticulously selecting isolation methods and resultant EV subpopulations based on the intended application.
    Keywords:  extracellular vesicles; isolation; mitochondria; proteomics
    DOI:  https://doi.org/10.1002/jex2.159
  13. Nat Genet. 2024 Jul 01.
    Mitochondrial genetics through the lens of single-cell multi-omics.
    Lena Nitsch, Caleb A Lareau, Leif S Ludwig.
      Mitochondria carry their own genetic information encoding for a subset of protein-coding genes and translational machinery essential for cellular respiration and metabolism. Despite its small size, the mitochondrial genome, its natural genetic variation and molecular phenotypes have been challenging to study using bulk sequencing approaches, due to its variation in cellular copy number, non-Mendelian modes of inheritance and propensity for mutations. Here we highlight emerging strategies designed to capture mitochondrial genetic variation across individual cells for lineage tracing and studying mitochondrial genetics in primary human cells and clinical specimens. We review recent advances surrounding single-cell mitochondrial genome sequencing and its integration with functional genomic readouts, including leveraging somatic mitochondrial DNA mutations as clonal markers that can resolve cellular population dynamics in complex human tissues. Finally, we discuss how single-cell whole mitochondrial genome sequencing approaches can be utilized to investigate mitochondrial genetics and its contribution to cellular heterogeneity and disease.
    DOI:  https://doi.org/10.1038/s41588-024-01794-8
  14. Mitochondrion. 2024 Jun 27. pii: S1567-7249(24)00085-0. [Epub ahead of print]78 101927
    mitoPADdb: A database of mitochondrial proteins associated with diseases.
    Jagannath Das, Sudipto Bhattacharjee, Sudipto Saha.
      Mitochondrial protein/gene mutations and expression variations contribute to the pathogenesis of various diseases, such as neurodegenerative and metabolic diseases. Detailed studies on mitochondrial protein-encoding (MPE) genes across diseases can provide clues for novel therapeutic strategies. Here, we collected, compiled, and manually curated the MPE gene mutation and expression variations data and their association with diseases in a single platform named mitoPADdb. The database contains 810 genes with 18,356 mutations and 1284 qualitative expression variations associated with 1793 diseases, grouped into 15 categories. It allows users to perform a comparative quantitative gene expression analysis for 317 transcriptomic studies across disease categories. Further, it provides information on MPE genes-associated molecular pathways. The mitoPADdb is a valuable resource for investigating mitochondrial dysfunction-related diseases. It can be accessed via http://bicresources.jcbose.ac.in/ssaha4/mitopaddb/index.html.
    Keywords:  Database; Diseases; Expression variation; Mitochondrial protein; Mutation; Pathway; Transcript expression
    DOI:  https://doi.org/10.1016/j.mito.2024.101927
  15. J Extracell Vesicles. 2024 Jul;13(7): e12458
    A systematic review and meta-analysis of clinical trials assessing safety and efficacy of human extracellular vesicle-based therapy.
    Mats Van Delen, Judith Derdelinckx, Kristien Wouters, Inge Nelissen, Nathalie Cools.
      Nowadays, it has become clear that extracellular vesicles (EVs) are not a cellular waste disposal vesicle but are an essential part of an intercellular communication system. Besides the use of EVs in biomarker studies and diagnostics, the potential of EV-therapeutics has been seen by many. They provide unique properties for disease therapy, including strong immune-modulatory actions, the possibility of engineering, low immunogenicity, and the capability of crossing biological barriers. Proof-of-concept of EV-therapeutics for various pathologies has been achieved in preclinical studies. However, clinical trials with EVs have only been emerging slowly. Here, we aim to provide a comprehensive overview of the current state-of-the-art concerning clinical studies using EVs in human therapy. By approaching the current knowledge in a systematic manner, we were able to include 21 reports for meta-analysis of safety and evaluation of efficacy outcomes. Overall, we have shown that EV-based therapy is safe with a low incidence of serious adverse events (SAE; 0.7% (95%-CI: 0.1-5.2%), and adverse events (AE; 4.4% (95%-CI: 0.7-22.2%). Subgroup analysis showed no significant difference in SAE when comparing autologous versus allogeneic administration, as well as engineered versus non-engineered EV products. A significantly higher number of AE was seen in autologous versus allogeneic administration. However, the clinical relevance remains questionable. Evaluation of the clinical outcomes of immunostimulatory, immunosuppressive or regenerative EV-therapies indicated improvement in the majority of treated patients. Despite these promising results, data need to be approached with caution due to a high heterogeneity in the EVs manufacturing methods, study design, and reporting of (S)AE. Overall, we conclude that EV-based therapy is safe and presents a promising opportunity in therapy. More efforts are needed in the standardization and harmonization of reporting of EV isolation and characterization data as well as in the reporting of (S)AE to allow inter-study comparison.
    Keywords:  clinical studies; exosome; extracellular vesicles; meta‐analysis; safety; systematic review; therapy
    DOI:  https://doi.org/10.1002/jev2.12458
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