bims-mitrat Biomed News
on Mitochondrial transplantation and transfer
Issue of 2024–06–16
thirteen papers selected by
Gökhan Burçin Kubat, Gulhane Health Sciences Institute
  1. Mitochondrial transplantation for ischemic heart disease.
  2. Mitochondrial transfer from Adipose stem cells to breast cancer cells drives multi-drug resistance.
  3. Mitochondrial membrane synthesis, remodelling and cellular trafficking.
  4. Regulation of mitochondrial network architecture and function in mesenchymal stem cells by micropatterned surfaces.
  5. Application of mesenchymal stem cells derived from the umbilical cord or Wharton's jelly and their extracellular vesicles in the treatment of various diseases.
  6. Colonocyte keratins stabilize mitochondria and contribute to mitochondrial energy metabolism.
  7. MTFP1 controls mitochondrial fusion to regulate inner membrane quality control and maintain mtDNA levels.
  8. Mitoregulin supports mitochondrial membrane integrity and protects against cardiac ischemia-reperfusion injury.
  9. Molecular pathways in mitochondrial disorders due to a defective mitochondrial protein synthesis.
  10. The interplay between mitophagy and mitochondrial ROS in acute lung injury.
  11. Regulation of cell function and identity by cellular senescence.
  12. Resveratrol impinges on retrograde communication without inducing mitochondrial biogenesis in aged rat soleus muscle.
  13. Interactions between extracellular vesicles and microbiome in human diseases: New therapeutic opportunities.
  1. Nat Nanotechnol. 2024 Jun 11.
    Mitochondrial transplantation for ischemic heart disease.
    Catherine Gorick, Anna Debski.
      
    DOI:  https://doi.org/10.1038/s41565-024-01678-2
  2. J Exp Clin Cancer Res. 2024 Jun 14. 43(1): 166
    Mitochondrial transfer from Adipose stem cells to breast cancer cells drives multi-drug resistance.
    Vitale Del Vecchio, Ayesha Rehman, Sameer Kumar Panda, Martina Torsiello, Martina Marigliano, Maria Maddalena Nicoletti, Giuseppe Andrea Ferraro, Vincenzo De Falco, Rosamaria Lappano, Eva Lieto, Francesca Pagliuca, Carlo Caputo, Marcella La Noce, Gianpaolo Papaccio, Virginia Tirino, Nirmal Robinson, Vincenzo Desiderio, Federica Papaccio.
       BACKGROUND: Breast cancer (BC) is a complex disease, showing heterogeneity in the genetic background, molecular subtype, and treatment algorithm. Historically, treatment strategies have been directed towards cancer cells, but these are not the unique components of the tumor bulk, where a key role is played by the tumor microenvironment (TME), whose better understanding could be crucial to obtain better outcomes.
    METHODS: We evaluated mitochondrial transfer (MT) by co-culturing Adipose stem cells with different Breast cancer cells (BCCs), through MitoTracker assay, Mitoception, confocal and immunofluorescence analyses. MT inhibitors were used to confirm the MT by Tunneling Nano Tubes (TNTs). MT effect on multi-drug resistance (MDR) was assessed using Doxorubicin assay and ABC transporter evaluation. In addition, ATP production was measured by Oxygen Consumption rates (OCR) and Immunoblot analysis.
    RESULTS: We found that MT occurs via Tunneling Nano Tubes (TNTs) and can be blocked by actin polymerization inhibitors. Furthermore, in hybrid co-cultures between ASCs and patient-derived organoids we found a massive MT. Breast Cancer cells (BCCs) with ASCs derived mitochondria (ADM) showed a reduced HIF-1α expression in hypoxic conditions, with an increased ATP production driving ABC transporters-mediated multi-drug resistance (MDR), linked to oxidative phosphorylation metabolism rewiring.
    CONCLUSIONS: We provide a proof-of-concept of the occurrence of Mitochondrial Transfer (MT) from Adipose Stem Cells (ASCs) to BC models. Blocking MT from ASCs to BCCs could be a new effective therapeutic strategy for BC treatment.
    Keywords:  Adipose Stem cells; Breast Cancer; Mitoception; Mitochondrial transfer; Multi-drug resistance; Tunneling nanotubes
    DOI:  https://doi.org/10.1186/s13046-024-03087-8
  3. J Inherit Metab Dis. 2024 Jun 14.
    Mitochondrial membrane synthesis, remodelling and cellular trafficking.
    Martina Messina, Frédéric M Vaz, Shamima Rahman.
      Mitochondria are dynamic cellular organelles with complex roles in metabolism and signalling. Primary mitochondrial disorders are a group of approximately 400 monogenic disorders arising from pathogenic genetic variants impacting mitochondrial structure, ultrastructure and/or function. Amongst these disorders, defects of complex lipid biosynthesis, especially of the unique mitochondrial membrane lipid cardiolipin, and membrane biology are an emerging group characterised by clinical heterogeneity, but with recurrent features including cardiomyopathy, encephalopathy, neurodegeneration, neuropathy and 3-methylglutaconic aciduria. This review discusses lipid synthesis in the mitochondrial membrane, the mitochondrial contact site and cristae organising system (MICOS), mitochondrial dynamics and trafficking, and the disorders associated with defects of each of these processes. We highlight overlapping functions of proteins involved in lipid biosynthesis and protein import into the mitochondria, pointing to an overarching coordination and synchronisation of mitochondrial functions. This review also focuses on membrane interactions between mitochondria and other organelles, namely the endoplasmic reticulum, peroxisomes, lysosomes and lipid droplets. We signpost disorders of these membrane interactions that may explain the observation of secondary mitochondrial dysfunction in heterogeneous pathological processes. Disruption of these organellar interactions ultimately impairs cellular homeostasis and organismal health, highlighting the central role of mitochondria in human health and disease.
    Keywords:  MAM; MERC; MICOS; cardiolipin; cell trafficking; mitochondrial lipid biosynthesis; organellar crosstalk; primary mitochondrial disease
    DOI:  https://doi.org/10.1002/jimd.12766
  4. Regen Biomater. 2024 ;11 rbae052
    Regulation of mitochondrial network architecture and function in mesenchymal stem cells by micropatterned surfaces.
    Zixuan Dong, Weiju Han, Panyu Jiang, Lijing Hao, Xiaoling Fu.
      Mitochondrial network architecture, which is closely related to mitochondrial function, is mechanically sensitive and regulated by multiple stimuli. However, the effects of microtopographic cues on mitochondria remain poorly defined. Herein, polycaprolactone (PCL) surfaces were used as models to investigate how micropatterns regulate mitochondrial network architecture and function in rat adipose-derived stem cells (rASCs). It was found that large pit (LP)-induced rASCs to form larger and more complex mitochondrial networks. Consistently, the expression of key genes related to mitochondrial dynamics revealed that mitochondrial fusion (MFN1 and MFN2) and midzone fission (DRP1 and MFF) were increased in rASCs on LP. In contrast, the middle pit (MP)-enhanced mitochondrial biogenesis, as evidenced by the larger mitochondrial area and higher expression of PGC-1. Both LP and MP promoted ATP production in rASCs. It is likely that LP increased ATP levels through modulating mitochondrial network architecture while MP stimulated mitochondria biogenesis to do so. Our study clarified the regulation of micropatterned surfaces on mitochondria, highlighting the potential of LP and MP as a simple platform to stimulate mitochondria and the subsequent cellular function of MSCs.
    Keywords:  mesenchymal stem cells; micropatterned surface; mitochondrial function; mitochondrial network architecture; regulation of mitochondria
    DOI:  https://doi.org/10.1093/rb/rbae052
  5. Tissue Cell. 2024 May 27. pii: S0040-8166(24)00116-2. [Epub ahead of print]89 102415
    Application of mesenchymal stem cells derived from the umbilical cord or Wharton's jelly and their extracellular vesicles in the treatment of various diseases.
    Ayyub Ali Patel, Asma'a H Mohamed, Jasur Rizaev, Ayaz Khurram Mallick, Maytham T Qasim, Waleed Al Abdulmonem, Azfar Jamal, Haroonrashid M Hattiwale, Mohammad Azhar Kamal, Fuzail Ahmad.
      Mesenchymal stem cells (MSCs) originating from the umbilical cord (UC) or Wharton's jelly (WJ) have attracted substantial interest due to their potential to augment therapeutic approaches for a wide range of disorders. These cells demonstrate a wide range of capabilities in the process of differentiating into a multitude of cell types. Additionally, they possess a significant capacity for proliferation and are conveniently accessible. Furthermore, they possess a status of being immune-privileged, exhibit minimal tumorigenic characteristics, and raise minimal ethical concerns. Consequently, they are well-suited candidates for tissue regeneration and the treatment of diseases. Additionally, UC-derived MSCs offer a substantial yield compared to other sources. The therapeutic effects of these MSCs are closely associated with the release of nanosized extracellular vesicles (EVs), including exosomes and microvesicles (MVs), containing lipids, microRNAs, and proteins that facilitate intercellular communication. Due to their reduced tumorigenic and immunogenic characteristics, in addition to their convenient manipulability, EVs have arisen as a viable alternative for the management of disorders. The favorable characteristics of UC-MSCs or WJ-MSCs and their EVs have generated significant attention in clinical investigations encompassing diverse pathologies. Therefore, we present a review encompassing current preclinical and clinical investigations, examining the implications of UC-MSCs in diverse diseases, including those affecting bone, cartilage, skin, liver, kidney, neural, lung, cardiovascular, muscle, and retinal tissues, as well as conditions like cancer, diabetes, sepsis, and others.
    Keywords:  Wharton’s jelly; exosomes; mesenchymal stromal cells; regenerative medicine; umbilical cord
    DOI:  https://doi.org/10.1016/j.tice.2024.102415
  6. Am J Physiol Gastrointest Liver Physiol. 2024 Jun 11.
    Colonocyte keratins stabilize mitochondria and contribute to mitochondrial energy metabolism.
    Joel H Nyström, Taina R H Heikkilä, Keshav Thapa, Ilari Pulli, Kid Törnquist, Diana M Toivola.
      Keratin intermediate filaments form dynamic filamentous networks, which provide mechanical stability, scaffolding and protection against stress to epithelial cells. Keratins and other intermediate filaments have been increasingly linked to the regulation of mitochondrial function and homeostasis in different tissues and cell types. While deletion of keratin 8 (K8‒/‒) in mouse colon elicits a colitis-like phenotype, epithelial hyperproliferation and blunted mitochondrial ketogenesis, the role for K8 in colonocyte mitochondrial function and energy metabolism is unknown. We used two K8 knockout mouse models and CRISPR/Cas9 K8‒/‒ colorectal adenocarcinoma Caco-2 cells to answer this question. The results show that K8‒/‒ colonocyte mitochondria in vivo are smaller and rounder, and that mitochondrial motility is increased in K8‒/‒ Caco-2 cells. Furthermore, K8-/- Caco-2 cells displayed diminished mitochondrial respiration and decreased mitochondrial membrane potential compared to controls, whereas glycolysis was not affected. The levels of mitochondrial respiratory chain complex proteins and mitochondrial regulatory proteins mitofusin-2 and prohibitin were decreased both in vitro in K8‒/‒ Caco-2 cells and in vivo in K8‒/‒ mouse colonocytes, and re-expression of K8 into K8‒/‒ Caco-2 cells normalizes the mitofusin-2 levels. Mitochondrial Ca2+ is an important regulator of mitochondrial energy metabolism and homeostasis, and Caco-2 cells lacking K8 displayed decreased levels and altered dynamics of mitochondrial matrix and cytoplasmic Ca2+. In summary, these novel findings attribute an important role for colonocyte K8 in stabilizing mitochondrial shape and movement and maintaining mitochondrial respiration and Ca2+ signaling. Further, how these metabolically compromised colonocytes are capable of hyperproliferating presents an intriguing question for future studies.
    Keywords:  Colon; Energy metabolism; Inflammatory Bowel Diseases; Keratins; Mitochondria
    DOI:  https://doi.org/10.1152/ajpgi.00220.2023
  7. Cell. 2024 Jun 05. pii: S0092-8674(24)00526-9. [Epub ahead of print]
    MTFP1 controls mitochondrial fusion to regulate inner membrane quality control and maintain mtDNA levels.
    Luis Carlos Tábara, Stephen P Burr, Michele Frison, Suvagata R Chowdhury, Vincent Paupe, Yu Nie, Mark Johnson, Jara Villar-Azpillaga, Filipa Viegas, Mayuko Segawa, Hanish Anand, Kasparas Petkevicius, Patrick F Chinnery, Julien Prudent.
      Mitochondrial dynamics play a critical role in cell fate decisions and in controlling mtDNA levels and distribution. However, the molecular mechanisms linking mitochondrial membrane remodeling and quality control to mtDNA copy number (CN) regulation remain elusive. Here, we demonstrate that the inner mitochondrial membrane (IMM) protein mitochondrial fission process 1 (MTFP1) negatively regulates IMM fusion. Moreover, manipulation of mitochondrial fusion through the regulation of MTFP1 levels results in mtDNA CN modulation. Mechanistically, we found that MTFP1 inhibits mitochondrial fusion to isolate and exclude damaged IMM subdomains from the rest of the network. Subsequently, peripheral fission ensures their segregation into small MTFP1-enriched mitochondria (SMEM) that are targeted for degradation in an autophagic-dependent manner. Remarkably, MTFP1-dependent IMM quality control is essential for basal nucleoid recycling and therefore to maintain adequate mtDNA levels within the cell.
    Keywords:  IMM quality control; IMM remodeling; MTFP1; autophagy; fission and fusion; mitochondria; mitochondrial dynamics; mitophagy; mtDNA
    DOI:  https://doi.org/10.1016/j.cell.2024.05.017
  8. bioRxiv. 2024 Jun 01. pii: 2024.05.31.596875. [Epub ahead of print]
    Mitoregulin supports mitochondrial membrane integrity and protects against cardiac ischemia-reperfusion injury.
    Colleen S Stein, Xiaoming Zhang, Nathan H Witmer, Edward Ross Pennington, Saame Raza Shaikh, Ryan L Boudreau.
      We and others discovered a highly-conserved mitochondrial transmembrane microprotein, named Mitoregulin (Mtln), that supports lipid metabolism. We reported that Mtln strongly binds cardiolipin (CL), increases mitochondrial respiration and Ca 2+ retention capacities, and reduces reactive oxygen species (ROS). Here we extend our observation of Mtln-CL binding and examine Mtln influence on cristae structure and mitochondrial membrane integrity during stress. We demonstrate that mitochondria from constitutive- and inducible Mtln-knockout (KO) mice are susceptible to membrane freeze-damage and that this can be rescued by acute Mtln re-expression. In mitochondrial-simulated lipid monolayers, we show that synthetic Mtln decreases lipid packing and monolayer elasticity. Lipidomics revealed that Mtln-KO heart tissues show broad decreases in 22:6-containing lipids and increased cardiolipin damage/remodeling. Lastly, we demonstrate that Mtln-KO mice suffer worse myocardial ischemia-reperfusion injury, hinting at a translationally-relevant role for Mtln in cardioprotection. Our work supports a model in which Mtln binds cardiolipin and stabilizes mitochondrial membranes to broadly influence diverse mitochondrial functions, including lipid metabolism, while also protecting against stress.
    DOI:  https://doi.org/10.1101/2024.05.31.596875
  9. Front Cell Dev Biol. 2024 ;12 1410245
    Molecular pathways in mitochondrial disorders due to a defective mitochondrial protein synthesis.
    Álvaro Antolínez-Fernández, Paula Esteban-Ramos, Miguel Ángel Fernández-Moreno, Paula Clemente.
      Mitochondria play a central role in cellular metabolism producing the necessary ATP through oxidative phosphorylation. As a remnant of their prokaryotic past, mitochondria contain their own genome, which encodes 13 subunits of the oxidative phosphorylation system, as well as the tRNAs and rRNAs necessary for their translation in the organelle. Mitochondrial protein synthesis depends on the import of a vast array of nuclear-encoded proteins including the mitochondrial ribosome protein components, translation factors, aminoacyl-tRNA synthetases or assembly factors among others. Cryo-EM studies have improved our understanding of the composition of the mitochondrial ribosome and the factors required for mitochondrial protein synthesis and the advances in next-generation sequencing techniques have allowed for the identification of a growing number of genes involved in mitochondrial pathologies with a defective translation. These disorders are often multisystemic, affecting those tissues with a higher energy demand, and often present with neurodegenerative phenotypes. In this article, we review the known proteins required for mitochondrial translation, the disorders that derive from a defective mitochondrial protein synthesis and the animal models that have been established for their study.
    Keywords:  OxPhos; mitochondria; mitochondrial disorders; mitoribosome; translation
    DOI:  https://doi.org/10.3389/fcell.2024.1410245
  10. Mitochondrion. 2024 Jun 12. pii: S1567-7249(24)00078-3. [Epub ahead of print] 101920
    The interplay between mitophagy and mitochondrial ROS in acute lung injury.
    Yizhi Zhong, Siwei Xia, Gaojian Wang, Qinxue Liu, Fengjie Ma, Yijin Yu, Yaping Zhang, Lu Qian, Li Hu, Junran Xie.
      Mitochondria orchestrate the production of new mitochondria and the removal of damaged ones to dynamically maintain mitochondrial homeostasis through constant biogenesis and clearance mechanisms. Mitochondrial quality control particularly relies on mitophagy, defined as selective autophagy with mitochondria-targeting specificity. Most ROS are derived from mitochondria, and the physiological concentration of mitochondrial ROS (mtROS) is no longer considered a useless by-product, as it has been proven to participate in immune and autophagy pathway regulation. However, excessive mtROS appears to be a pathogenic factor in several diseases, including acute lung injury (ALI). The interplay between mitophagy and mtROS is complex and closely related to ALI. Here, we review the pathways of mitophagy, the intricate relationship between mitophagy and mtROS, the role of mtROS in the pathogenesis of ALI, and their effects and related progression in ALI induced by different conditions.
    Keywords:  Acute lung injury; Mechanism; Mitochondrial reactive oxygen species; Mitophagy; Oxidative stress
    DOI:  https://doi.org/10.1016/j.mito.2024.101920
  11. J Cell Biol. 2024 Aug 05. pii: e202401112. [Epub ahead of print]223(8):
    Regulation of cell function and identity by cellular senescence.
    Anda Huna, Amélie Massemin, Gabriela Makulyte, Jean-Michel Flaman, Nadine Martin, David Bernard.
      During aging and in some contexts, like embryonic development, wound healing, and diseases such as cancer, senescent cells accumulate and play a key role in different pathophysiological functions. A long-held belief was that cellular senescence decreased normal cell functions, given the loss of proliferation of senescent cells. This view radically changed following the discovery of the senescence-associated secretory phenotype (SASP), factors released by senescent cells into their microenvironment. There is now accumulating evidence that cellular senescence also promotes gain-of-function effects by establishing, reinforcing, or changing cell identity, which can have a beneficial or deleterious impact on pathophysiology. These effects may involve both proliferation arrest and autocrine SASP production, although they largely remain to be defined. Here, we provide a historical overview of the first studies on senescence and an insight into emerging trends regarding the effects of senescence on cell identity.
    DOI:  https://doi.org/10.1083/jcb.202401112
  12. Exp Gerontol. 2024 Jun 12. pii: S0531-5565(24)00127-X. [Epub ahead of print] 112485
    Resveratrol impinges on retrograde communication without inducing mitochondrial biogenesis in aged rat soleus muscle.
    Rosa Di Lorenzo, Guglielmina Chimienti, Anna Picca, Lucia Trisolini, Tiziana Latronico, Grazia Maria Liuzzi, Vito Pesce, Christiaan Leuweenburgh, Angela Maria Serena Lezza.
      The natural polyphenol resveratrol (RSV) might counteract the skeletal muscle age-related loss of muscle mass and strength/function partly acting on mitochondria. This work analysed the effects of a six-week administration of RSV (50 mg/kg/day) in the oxidative Soleus (Sol) skeletal muscle of old rats (27 months old). RSV effects on key mitochondrial biogenesis proteins led to un unchanged amount of SIRT1 protein and a marked decrease (60 %) in PGC-1α protein. In addition, Peroxyredoxin 3 (PRXIII) protein decreased by 50 %, which on overall suggested the absence of induction of mitochondrial biogenesis by RSV in old Sol. A novel direct correlation between PGC-1α and PRXIII proteins was demonstrated by correlation analysis in RSV and ad-libitum (AL) rats, supporting the reciprocally coordinated expression of the proteins. RSV supplementation led to an unexpected 50 % increase in the frequency of the oxidized base OH8dG in mtDNA. Furthermore, RSV supplementation induced a 50 % increase in the DRP1 protein of mitochondrial dynamics. In both rat groups an inverse correlation between PGC-1α and the frequency of OH8dG as well as an inverse correlation between PRXIII and the frequency of OH8dG were also found, suggestive of a relationship between oxidative damage to mtDNA and mitochondrial biogenesis activity. Such results may indicate that the antioxidant activity of RSV in aged Sol impinged on the oxidative fiber-specific, ROS-mediated, retrograde communication, thereby affecting the expression of SIRT1, PGC-1α and PRXIII, reducing the compensatory responses to the age-related mitochondrial oxidative stress and decline.
    Keywords:  Mitochondrial biogenesis; Rat soleus skeletal muscle; Resveratrol
    DOI:  https://doi.org/10.1016/j.exger.2024.112485
  13. Imeta. 2023 May;2(2): e86
    Interactions between extracellular vesicles and microbiome in human diseases: New therapeutic opportunities.
    Rongjin Luo, Yanmin Chang, Huaizhen Liang, Weifeng Zhang, Yu Song, Gaocai Li, Cao Yang.
      In recent decades, accumulating research on the interactions between microbiome homeostasis and host health has broadened new frontiers in delineating the molecular mechanisms of disease pathogenesis and developing novel therapeutic strategies. By transporting proteins, nucleic acids, lipids, and metabolites in their versatile bioactive molecules, extracellular vesicles (EVs), natural bioactive cell-secreted nanoparticles, may be key mediators of microbiota-host communications. In addition to their positive and negative roles in diverse physiological and pathological processes, there is considerable evidence to implicate EVs secreted by bacteria (bacterial EVs [BEVs]) in the onset and progression of various diseases, including gastrointestinal, respiratory, dermatological, neurological, and musculoskeletal diseases, as well as in cancer. Moreover, an increasing number of studies have explored BEV-based platforms to design novel biomedical diagnostic and therapeutic strategies. Hence, in this review, we highlight the recent advances in BEV biogenesis, composition, biofunctions, and their potential involvement in disease pathologies. Furthermore, we introduce the current and emerging clinical applications of BEVs in diagnostic analytics, vaccine design, and novel therapeutic development.
    Keywords:  biotherapy; extracellular vesicles; microbiome; microbiome–host interaction; vaccine
    DOI:  https://doi.org/10.1002/imt2.86
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