bims-mitrat 2024-04-28 papers

bims-mitrat

Biomed News

on Mitochondrial Transplantation and Transfer

Issue of 2024‒04‒28
nineteen papers selected by
Gökhan Burçin Kubat, Gulhane Health Sciences Institute

Mitochondrial Transplantation's Role in Rodent Skeletal Muscle Bioenergetics: Recharging the Engine of Aging.
Restoring Mitochondrial Function and Muscle Satellite Cell Signaling: Remedies against Age-Related Sarcopenia.
Mitochondrial sites of contact with the nucleus.
The interplay between hippo signaling and mitochondrial metabolism: Implications for cellular homeostasis and disease.
Intranasal Administration of Mesenchymal Stem Cell-Derived Exosome Alleviates Hypoxic-Ischemic Brain Injury.
Organ-Specific Mitochondrial Alterations Following Ischemia-Reperfusion Injury in Post-Cardiac Arrest Syndrome: A Comprehensive Review.
MSC-derived mitochondria promote axonal regeneration via Atf3 gene up-regulation by ROS induced DNA double strand breaks at transcription initiation region.
Unlocking mitochondrial drug targets: The importance of mitochondrial transport proteins.
Protein insertion into the inner membrane of mitochondria: routes and mechanisms.
Combining sophisticated fast FLIM, confocal microscopy, and STED nanoscopy for live-cell imaging of tunneling nanotubes.
Effect of the Mitochondrial Transaminase (GOT2) on Membrane Potential Sensitive Respiration in Mitochondria of Differentiated C2C12 Muscle Cells.
The complexity of extracellular vesicles: Bridging the gap between cellular communication and neuropathology.
Small extracellular vesicles derived from human mesenchymal stem cells prevent Th17-dominant neutrophilic airway inflammation via immunoregulation on Th17 cells.
Characterization of the Mitochondrial Proteome in the Ctenophore Mnemiopsis leidyi Using MitoPredictor.
Investigation of the Nanoparticulation Method and Cell-Killing Effect following the Mitochondrial Delivery of Hydrophobic Porphyrin-Based Photosensitizers.
The role of mitochondrial dynamics and mitophagy in skeletal muscle atrophy: from molecular mechanisms to therapeutic insights.
Mitochondrial dysfunction, a weakest link of network of aging, relation to innate intramitochondrial immunity of DNA recognition receptors.
Progress of Mitochondrial Function Regulation in Cardiac Regeneration.
Exosomal miR-9-5p derived from iPSC-MSCs ameliorates doxorubicin-induced cardiomyopathy by inhibiting cardiomyocyte senescence.

Biomolecules. 2024 Apr 18. pii: 493. [Epub ahead of print]14(4):

Mitochondrial Transplantation's Role in Rodent Skeletal Muscle Bioenergetics: Recharging the Engine of Aging.

Tasnim Arroum, Gerald A Hish, Kyle J Burghardt, James D McCully, Maik Hüttemann, Moh H Malek.

  BACKGROUND: Mitochondria are the 'powerhouses of cells' and progressive mitochondrial dysfunction is a hallmark of aging in skeletal muscle. Although different forms of exercise modality appear to be beneficial to attenuate aging-induced mitochondrial dysfunction, it presupposes that the individual has a requisite level of mobility. Moreover, non-exercise alternatives (i.e., nutraceuticals or pharmacological agents) to improve skeletal muscle bioenergetics require time to be effective in the target tissue and have another limitation in that they act systemically and not locally where needed. Mitochondrial transplantation represents a novel directed therapy designed to enhance energy production of tissues impacted by defective mitochondria. To date, no studies have used mitochondrial transplantation as an intervention to attenuate aging-induced skeletal muscle mitochondrial dysfunction. The purpose of this investigation, therefore, was to determine whether mitochondrial transplantation can enhance skeletal muscle bioenergetics in an aging rodent model. We hypothesized that mitochondrial transplantation would result in sustained skeletal muscle bioenergetics leading to improved functional capacity.METHODS: Fifteen female mice (24 months old) were randomized into two groups (placebo or mitochondrial transplantation). Isolated mitochondria from a donor mouse of the same sex and age were transplanted into the hindlimb muscles of recipient mice (quadriceps femoris, tibialis anterior, and gastrocnemius complex).
RESULTS: The results indicated significant increases (ranging between ~36% and ~65%) in basal cytochrome c oxidase and citrate synthase activity as well as ATP levels in mice receiving mitochondrial transplantation relative to the placebo. Moreover, there were significant increases (approx. two-fold) in protein expression of mitochondrial markers in both glycolytic and oxidative muscles. These enhancements in the muscle translated to significant improvements in exercise tolerance.
CONCLUSIONS: This study provides initial evidence showing how mitochondrial transplantation can promote skeletal muscle bioenergetics in an aging rodent model.

Keywords:  endurance; energy production; exercise physiology

DOI:  https://doi.org/10.3390/biom14040493
Biomolecules. 2024 Mar 28. pii: 415. [Epub ahead of print]14(4):

Restoring Mitochondrial Function and Muscle Satellite Cell Signaling: Remedies against Age-Related Sarcopenia.

Emanuele Marzetti, Biliana Lozanoska-Ochser, Riccardo Calvani, Francesco Landi, Hélio José Coelho-Júnior, Anna Picca.

  Sarcopenia has a complex pathophysiology that encompasses metabolic dysregulation and muscle ultrastructural changes. Among the drivers of intracellular and ultrastructural changes of muscle fibers in sarcopenia, mitochondria and their quality control pathways play relevant roles. Mononucleated muscle stem cells/satellite cells (MSCs) have been attributed a critical role in muscle repair after an injury. The involvement of mitochondria in supporting MSC-directed muscle repair is unclear. There is evidence that a reduction in mitochondrial biogenesis blunts muscle repair, thus indicating that the delivery of functional mitochondria to injured muscles can be harnessed to limit muscle fibrosis and enhance restoration of muscle function. Injection of autologous respiration-competent mitochondria from uninjured sites to damaged tissue has been shown to reduce infarct size and enhance cell survival in preclinical models of ischemia-reperfusion. Furthermore, the incorporation of donor mitochondria into MSCs enhances lung and cardiac tissue repair. This strategy has also been tested for regeneration purposes in traumatic muscle injuries. Indeed, the systemic delivery of mitochondria promotes muscle regeneration and restores muscle mass and function while reducing fibrosis during recovery after an injury. In this review, we discuss the contribution of altered MSC function to sarcopenia and illustrate the prospect of harnessing mitochondrial delivery and restoration of MSCs as a therapeutic strategy against age-related sarcopenia.

Keywords:  aging; cytokines; inflammation; mitochondrial dysfunction; mitochondrial-derived vesicles; muscle fibrosis; muscle injury; muscle satellite cells; muscle wasting; skeletal muscle fibers

DOI:  https://doi.org/10.3390/biom14040415
J Cell Biol. 2024 Jun 03. pii: e202305010. [Epub ahead of print]223(6):

Mitochondrial sites of contact with the nucleus.

Michelangelo Campanella, Brindha Kannan.

Membrane contact sites (MCS) between mitochondria and the nucleus have been recently described. Termed nucleus associated mitochondria (NAM), they prime the expression of genes required for cellular resistance to stressors, thus offering a tethering mechanism for homeostatic communication. Here, we discuss the composition of NAM and their physiological and pathological significance.

DOI: https://doi.org/10.1083/jcb.202305010
Mitochondrion. 2024 Apr 21. pii: S1567-7249(24)00043-6. [Epub ahead of print]76 101885

The interplay between hippo signaling and mitochondrial metabolism: Implications for cellular homeostasis and disease.

Priyanka Biswal, Manas Ranjan Sahu, Mir Hilal Ahmad, Amal Chandra Mondal.

  Mitochondria are the membrane-bound organelles producing energy for cellular metabolic processes. They orchestrate diverse cell signaling cascades regulating cellular homeostasis. This functional versatility may be attributed to their ability to regulate mitochondrial dynamics, biogenesis, and apoptosis. The Hippo pathway, a conserved signaling pathway, regulates various cellular processes, including mitochondrial functions. Through its effectors YAP and TAZ, the Hippo pathway regulates transcription factors and creates a seriatim process that mediates cellular metabolism, mitochondrial dynamics, and survival. Mitochondrial dynamics also potentially regulates Hippo signaling activation, indicating a bidirectional relationship between the two. This review outlines the interplay between the Hippo signaling components and the multifaceted role of mitochondria in cellular homeostasis under physiological and pathological conditions.

Keywords:  Apoptosis; Hippo signaling; Mitochondrial biogenesis; Mitochondrial dynamics; Mitophagy; Oxidative stress

DOI:  https://doi.org/10.1016/j.mito.2024.101885
Pharmaceutics. 2024 Mar 23. pii: 446. [Epub ahead of print]16(4):

Intranasal Administration of Mesenchymal Stem Cell-Derived Exosome Alleviates Hypoxic-Ischemic Brain Injury.

Takuma Ikeda, Masahito Kawabori, Yuyuan Zheng, Sho Yamaguchi, Shuho Gotoh, Yo Nakahara, Erika Yoshie, Miki Fujimura.

  Hypoxic-ischemic brain injury arises from inadequate oxygen delivery to the brain, commonly occurring following cardiac arrest, which lacks effective treatments. Recent studies have demonstrated the therapeutic potential of exosomes released from mesenchymal stem cells. Given the challenge of systemic dilution associated with intravenous administration, intranasal delivery has emerged as a promising approach. In this study, we investigate the effects of intranasally administered exosomes in an animal model. Exosomes were isolated from the cell supernatants using the ultracentrifugation method. Brain injury was induced in Sprague-Dawley rats through a transient four-vessel occlusion model. Intranasal administration was conducted with 3 × 108 exosome particles in 20 µL of PBS or PBS alone, administered daily for 7 days post-injury. Long-term cognitive behavioral assessments, biodistribution of exosomes, and histological evaluations of apoptosis and neuroinflammation were conducted. Exosomes were primarily detected in the olfactory bulb one hour after intranasal administration, subsequently distributing to the striatum and midbrain. Rats treated with exosomes exhibited substantial improvement in cognitive function up to 28 days after the insult, and demonstrated significantly fewer apoptotic cells along with higher neuronal cell survival in the hippocampus. Exosomes were found to be taken up by microglia, leading to a decrease in the expression of cytotoxic inflammatory markers.

Keywords:  exosome; hypoxic-ischemic brain injury; inflammation; intranasal administration; mesenchymal stem cell

DOI:  https://doi.org/10.3390/pharmaceutics16040446
Life (Basel). 2024 Apr 05. pii: 477. [Epub ahead of print]14(4):

Organ-Specific Mitochondrial Alterations Following Ischemia-Reperfusion Injury in Post-Cardiac Arrest Syndrome: A Comprehensive Review.

Eriko Nakamura, Tomoaki Aoki, Yusuke Endo, Jacob Kazmi, Jun Hagiwara, Cyrus E Kuschner, Tai Yin, Junhwan Kim, Lance B Becker, Kei Hayashida.

  BACKGROUND: Mitochondrial dysfunction, which is triggered by systemic ischemia-reperfusion (IR) injury and affects various organs, is a key factor in the development of post-cardiac arrest syndrome (PCAS). Current research on PCAS primarily addresses generalized mitochondrial responses, resulting in a knowledge gap regarding organ-specific mitochondrial dynamics. This review focuses on the organ-specific mitochondrial responses to IR injury, particularly examining the brain, heart, and kidneys, to highlight potential therapeutic strategies targeting mitochondrial dysfunction to enhance outcomes post-IR injury.METHODS AND RESULTS: We conducted a narrative review examining recent advancements in mitochondrial research related to IR injury. Mitochondrial responses to IR injury exhibit considerable variation across different organ systems, influenced by unique mitochondrial structures, bioenergetics, and antioxidative capacities. Each organ demonstrates distinct mitochondrial behaviors that have evolved to fulfill specific metabolic and functional needs. For example, cerebral mitochondria display dynamic responses that can be both protective and detrimental to neuronal activity and function during ischemic events. Cardiac mitochondria show vulnerability to IR-induced oxidative stress, while renal mitochondria exhibit a unique pattern of fission and fusion, closely linked to their susceptibility to acute kidney injury. This organ-specific heterogeneity in mitochondrial responses requires the development of tailored interventions. Progress in mitochondrial medicine, especially in the realms of genomics and metabolomics, is paving the way for innovative strategies to combat mitochondrial dysfunction. Emerging techniques such as mitochondrial transplantation hold the potential to revolutionize the management of IR injury in resuscitation science.
CONCLUSIONS: The investigation into organ-specific mitochondrial responses to IR injury is pivotal in the realm of resuscitation research, particularly within the context of PCAS. This nuanced understanding holds the promise of revolutionizing PCAS management, addressing the unique mitochondrial dysfunctions observed in critical organs affected by IR injury.

Keywords:  acute kidney injury; cardiac arrest; cardiac injury; ischemia; ischemic stroke; mitochondria; reperfusion injury

DOI:  https://doi.org/10.3390/life14040477
Cell Commun Signal. 2024 Apr 25. 22(1): 240

MSC-derived mitochondria promote axonal regeneration via Atf3 gene up-regulation by ROS induced DNA double strand breaks at transcription initiation region.

Yingchi Zhang, Tao Xu, Jie Xie, Hua Wu, Weihua Hu, Xuefeng Yuan.

  BACKGROUND: The repair of peripheral nerve injury poses a clinical challenge, necessitating further investigation into novel therapeutic approaches. In recent years, bone marrow mesenchymal stromal cell (MSC)-derived mitochondrial transfer has emerged as a promising therapy for cellular injury, with reported applications in central nerve injury. However, its potential therapeutic effect on peripheral nerve injury remains unclear.METHODS: We established a mouse sciatic nerve crush injury model. Mitochondria extracted from MSCs were intraneurally injected into the injured sciatic nerves. Axonal regeneration was observed through whole-mount nerve imaging. The dorsal root ganglions (DRGs) corresponding to the injured nerve were harvested to test the gene expression, reactive oxygen species (ROS) levels, as well as the degree and location of DNA double strand breaks (DSBs).
RESULTS: The in vivo experiments showed that the mitochondrial injection therapy effectively promoted axon regeneration in injured sciatic nerves. Four days after injection of fluorescently labeled mitochondria into the injured nerves, fluorescently labeled mitochondria were detected in the corresponding DRGs. RNA-seq and qPCR results showed that the mitochondrial injection therapy enhanced the expression of Atf3 and other regeneration-associated genes in DRG neurons. Knocking down of Atf3 in DRGs by siRNA could diminish the therapeutic effect of mitochondrial injection. Subsequent experiments showed that mitochondrial injection therapy could increase the levels of ROS and DSBs in injury-associated DRG neurons, with this increase being correlated with Atf3 expression. ChIP and Co-IP experiments revealed an elevation of DSB levels within the transcription initiation region of the Atf3 gene following mitochondrial injection therapy, while also demonstrating a spatial proximity between mitochondria-induced DSBs and CTCF binding sites.
CONCLUSION: These findings suggest that MSC-derived mitochondria injected into the injured nerves can be retrogradely transferred to DRG neuron somas via axoplasmic transport, and increase the DSBs at the transcription initiation regions of the Atf3 gene through ROS accumulation, which rapidly release the CTCF-mediated topological constraints on chromatin interactions. This process may enhance spatial interactions between the Atf3 promoter and enhancer, ultimately promoting Atf3 expression. The up-regulation of Atf3 induced by mitochondria further promotes the expression of downstream regeneration-associated genes and facilitates axon regeneration.

Keywords:  Activating transcription factor 3; Axonal regeneration; Bone marrow mesenchymal stromal cell; DNA double strand break; Peripheral nerve injury

DOI:  https://doi.org/10.1186/s12964-024-01617-7
Acta Physiol (Oxf). 2024 Apr 26. e14150

Unlocking mitochondrial drug targets: The importance of mitochondrial transport proteins.

Charlotte A Hoogstraten, Tom J J Schirris, Frans G M Russel.

  A disturbed mitochondrial function contributes to the pathology of many common diseases. These organelles are therefore important therapeutic targets. On the contrary, many adverse effects of drugs can be explained by a mitochondrial off-target effect, in particular, due to an interaction with carrier proteins in the inner membrane. Yet this class of transport proteins remains underappreciated and understudied. The aim of this review is to provide a deeper understanding of the role of mitochondrial carriers in health and disease and their significance as drug targets. We present literature-based evidence that mitochondrial carrier proteins are associated with prevalent diseases and emphasize their potential as drug (off-)target sites by summarizing known mitochondrial drug-transporter interactions. Studying these carriers will enhance our knowledge of mitochondrial drug on- and off-targets and provide opportunities to further improve the efficacy and safety of drugs.

Keywords:  carrier proteins; drugs; efficacy and safety; inner mitochondrial membrane; mitochondria; on‐ and off‐target

DOI:  https://doi.org/10.1111/apha.14150
FEBS Open Bio. 2024 Apr 25.

Protein insertion into the inner membrane of mitochondria: routes and mechanisms.

Büsra Kizmaz, Annika Nutz, Annika Egeler, Johannes M Herrmann.

  The inner membrane of mitochondria contains hundreds of different integral membrane proteins. These proteins transport molecules into and out of the matrix, they carry out multifold catalytic reactions and they promote the biogenesis or degradation of mitochondrial constituents. Most inner membrane proteins are encoded by nuclear genes and synthesized in the cytosol from where they are imported into mitochondria by translocases in the outer and inner membrane. Three different import routes direct proteins into the inner membrane and allow them to acquire their appropriate membrane topology. First, mitochondrial import intermediates can be arrested at the level of the TIM23 inner membrane translocase by a stop-transfer sequence to reach the inner membrane by lateral insertion. Second, proteins can be fully translocated through the TIM23 complex into the matrix from where they insert into the inner membrane in an export-like reaction. Carriers and other polytopic membrane proteins embark on a third insertion pathway: these hydrophobic proteins employ the specialized TIM22 translocase to insert from the intermembrane space (IMS) into the inner membrane. This review article describes these three targeting routes and provides an overview of the machinery that promotes the topogenesis of mitochondrial inner membrane proteins.

Keywords:  TIM22 complex; TIM23 complex; carrier proteins; membrane proteins; mitochondria; protein import

DOI:  https://doi.org/10.1002/2211-5463.13806
Life Sci Alliance. 2024 Jul;pii: e202302398. [Epub ahead of print]7(7):

Combining sophisticated fast FLIM, confocal microscopy, and STED nanoscopy for live-cell imaging of tunneling nanotubes.

Magalie Bénard, Christophe Chamot, Damien Schapman, Aurélien Debonne, Alexis Lebon, Fatéméh Dubois, Guénaëlle Levallet, Hitoshi Komuro, Ludovic Galas.

Cell-to-cell communication via tunneling nanotubes (TNTs) is a challenging topic with a growing interest. In this work, we proposed several innovative tools that use red/near-infrared dye labeling and employ lifetime-based imaging strategies to investigate the dynamics of TNTs in a living mesothelial H28 cell line that exhibits spontaneously TNT1 and TNT2 subtypes. Thanks to a fluorescence lifetime imaging microscopy module being integrated into confocal microscopy and stimulated emission depletion nanoscopy, we applied lifetime imaging, lifetime dye unmixing, and lifetime denoising techniques to perform multiplexing experiments and time-lapses of tens of minutes, revealing therefore structural and functional characteristics of living TNTs that were preserved from light exposure. In these conditions, vesicle-like structures, and tubular- and round-shaped mitochondria were identified within living TNT1. In addition, mitochondrial dynamic studies revealed linear and stepwise mitochondrial migrations, bidirectional movements, transient backtracking, and fission events in TNT1. Transfer of Nile Red-positive puncta via both TNT1 and TNT2 was also detected between living H28 cells.

DOI: https://doi.org/10.26508/lsa.202302398
Am J Physiol Cell Physiol. 2024 Apr 22.

Effect of the Mitochondrial Transaminase (GOT2) on Membrane Potential Sensitive Respiration in Mitochondria of Differentiated C2C12 Muscle Cells.

Ritu Som, Brian D Fink, Liping Yu, William I Sivitz.

  We previously showed that the transaminase inhibitor, aminooxyacetic acid, reduced respiration energized at complex II (succinate dehydrogenase, SDH) in mitochondria isolated from mouse hindlimb muscle. The effect required a reduction in membrane potential with resultant accumulation of oxaloacetate (OAA), a potent inhibitor of SDH. To specifically assess the effect of the mitochondrial transaminase, glutamic oxaloacetic transaminase (GOT2) on complex II respiration and to determine the effect in intact cells as well as isolated mitochondria, we performed respiratory and metabolic studies in wildtype (WT) and CRISPR-generated GOT2 knockdown (KD) C2C12 myocytes. Intact cell respiration by GOT2KD cells versus WT was reduced by adding carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP) to lower potential. In mitochondria of C2C12 KD cells, respiration at low potential generated by 1µM FCCP and energized at complex II by 10mM succinate + 0.5mM glutamate, (but not by complex I substrates) was reduced versus WT mitochondria. Although we could not detect OAA, metabolite data suggested that OAA inhibition of SDH may have contributed to the FCCP effect. C2C12 mitochondria differed from skeletal muscle mitochondria in that the effect of FCCP on complex II respiration was not evident with ADP addition. We also observed that C2C12 cells, unlike skeletal muscle, expressed glutamate dehydrogenase, which competes with GOT2 for glutamate metabolism. In summary, GOT2 KD reduced C2C12 respiration in intact cells at low potential. From differential substrate effects, this occurred largely at complex II. Moreover, C2C12 versus muscle mitochondria differ in complex II sensitivity to ADP and differ markedly in expression of glutamate dehydrogenase.

Keywords:  aspartate aminotransferase; mitochondria; myocytes; oxaloacetate; succinate dehydrogenase

DOI:  https://doi.org/10.1152/ajpcell.00576.2023
J Neurochem. 2024 Apr 22.

The complexity of extracellular vesicles: Bridging the gap between cellular communication and neuropathology.

Stephanie Tam, Darcy Wear, Christopher D Morrone, Wai Haung Yu.

  Brain-derived extracellular vesicles (EVs) serve a prominent role in maintaining homeostasis and contributing to pathology in health and disease. This review establishes a crucial link between physiological processes leading to EV biogenesis and their impacts on disease. EVs are involved in the clearance and transport of proteins and nucleic acids, responding to changes in cellular processes associated with neurodegeneration, including autophagic disruption, organellar dysfunction, aging, and other cell stresses. In neurodegenerative disorders (e.g., Alzheimer's disease, Parkinson's disease, etc.), EVs contribute to the spread of pathological proteins like amyloid β, tau, ɑ-synuclein, prions, and TDP-43, exacerbating neurodegeneration and accelerating disease progression. Despite evidence for both neuropathological and neuroprotective effects of EVs, the mechanistic switch between their physiological and pathological functions remains elusive, warranting further research into their involvement in neurodegenerative disease. Moreover, owing to their innate ability to traverse the blood-brain barrier and their ubiquitous nature, EVs emerge as promising candidates for novel diagnostic and therapeutic strategies. The review uniquely positions itself at the intersection of EV cell biology, neurophysiology, and neuropathology, offering insights into the diverse biological roles of EVs in health and disease.

Keywords:  autophagy; extracellular vesicle; neurodegeneration; proteostasis; translation

DOI:  https://doi.org/10.1111/jnc.16108
Int Immunopharmacol. 2024 Apr 25. pii: S1567-5769(24)00644-1. [Epub ahead of print]133 112126

Small extracellular vesicles derived from human mesenchymal stem cells prevent Th17-dominant neutrophilic airway inflammation via immunoregulation on Th17 cells.

Bi-Xin He, Shu-Bing Fang, Ying-Chun Xie, Dong-Xiao Lou, Zi-Cong Wu, Chan-Gu Li, Xiao-Qing Liu, Zhi-Rou Zhou, Long-Xin Huang, Tian Tian, De-Hua Chen, Qing-Ling Fu.

  Type 17 helper T cells (Th17)-dominant neutrophilic airway inflammation is critical in the pathogenesis of steroid-resistant airway inflammation such as severe asthma. Small extracellular vesicles (sEV) derived from human mesenchymal stem cells (MSCs) display extensive therapeutic effects and advantages in many diseases. However, the role of MSC-sEV in Th17-dominant neutrophilic airway inflammation and the related mechanisms are still poorly studied. Here we found that MSC-sEV significantly alleviated the infiltration of inflammatory cells in peribronchial interstitial tissues and reduced levels of inflammatory cells, especially neutrophils, in bronchoalveolar lavage fluids (BALF) of mice with neutrophilic airway inflammation. Consistently, MSC-sEV significantly decreased levels of IL-17A in BALF and Th17 in lung tissues. Furthermore, we found that labelled MSC-sEV were taken up by human CD4+ T cells most obviously at 12 h after incubation, and distributed mostly in mouse lungs. More importantly, potential signaling pathways involved in the MSC-sEV mediated inhibition of Th17 polarization were found using RNA sequencing. Using Western blot, JAK2-STAT3 pathway was identified as an important role in the inhibition of Th17 polarization by MSC-sEV. We found that proteins in MSC-sEV were mostly involved in the therapeutic effects of MSC-sEV. In total, our study suggested that MSC-sEV could be a potential therapeutic strategy for the treatment of neutrophilic airway inflammation.

Keywords:  Extracellular vesicles; Immunoregulation; Mesenchymal stem cells; Neutrophilic airway inflammation; Type 17 helper cells

DOI:  https://doi.org/10.1016/j.intimp.2024.112126
Methods Mol Biol. 2024 ;2757 239-257

Characterization of the Mitochondrial Proteome in the Ctenophore Mnemiopsis leidyi Using MitoPredictor.

Viraj Muthye, Dennis V Lavrov.

  Mitochondrial proteomes have been experimentally characterized for only a handful of animal species. However, the increasing availability of genomic and transcriptomic data allows one to infer mitochondrial proteins using computational tools. MitoPredictor is a novel random forest classifier, which utilizes orthology search, mitochondrial targeting signal (MTS) identification, and protein domain content to infer mitochondrial proteins in animals. MitoPredictor's output also includes an easy-to-use R Shiny applet for the visualization and analysis of the results. In this article, we provide a guide for predicting and analyzing the mitochondrial proteome of the ctenophore Mnemiopsis leidyi using MitoPredictor.

Keywords:  Ctenophora; Machine learning; MitoPredictor; Mitochondria; Mnemiopsis; Proteome; Random Forest

DOI:  https://doi.org/10.1007/978-1-0716-3642-8_10
Int J Mol Sci. 2024 Apr 12. pii: 4294. [Epub ahead of print]25(8):

Investigation of the Nanoparticulation Method and Cell-Killing Effect following the Mitochondrial Delivery of Hydrophobic Porphyrin-Based Photosensitizers.

Rina Naganawa, Hanjun Zhao, Yuta Takano, Masatoshi Maeki, Manabu Tokeshi, Hideyoshi Harashima, Yuma Yamada.

  Photodynamic therapy is expected to be a less invasive treatment, and strategies for targeting mitochondria, the main sources of singlet oxygen, are attracting attention to increase the efficacy of photodynamic therapy and reduce its side effects. To date, we have succeeded in encapsulating the photosensitizer rTPA into MITO-Porter (MP), a mitochondria-targeted Drug Delivery System (DDS), aimed at mitochondrial delivery of the photosensitizer while maintaining its activity. In this study, we report the results of our studies to alleviate rTPA aggregation in an effort to improve drug efficacy and assess the usefulness of modifying the rTPA side chain to improve the mitochondrial retention of MITO-Porter, which exhibits high therapeutic efficacy. Conventional rTPA with anionic side chains and two rTPA analogs with side chains that were converted to neutral or cationic side chains were encapsulated into MITO-Porter. Low-MP (MITO-Porter with Low Drug/Lipid) exhibited high drug efficacy for all three types of rTPA, and in Low-MP, charged rTPA-encapsulated MP exhibited high drug efficacy. The cellular uptake and mitochondrial translocation capacities were similar for all particles, suggesting that differences in aggregation rates during the incorporation of rTPA into MITO-Porter resulted in differences in drug efficacy.

Keywords:  MITO-Porter; mitochondria; mitochondrial delivery; photodynamic therapy; photosensitizer

DOI:  https://doi.org/10.3390/ijms25084294
Cell Mol Biol Lett. 2024 Apr 23. 29(1): 59

The role of mitochondrial dynamics and mitophagy in skeletal muscle atrophy: from molecular mechanisms to therapeutic insights.

Yuhang Lei, Mailin Gan, Yanhao Qiu, Qiuyang Chen, Xingyu Wang, Tianci Liao, Mengying Zhao, Lei Chen, Shunhua Zhang, Ye Zhao, Lili Niu, Yan Wang, Li Zhu, Linyuan Shen.

  Skeletal muscle is the largest metabolic organ of the human body. Maintaining the best quality control and functional integrity of mitochondria is essential for the health of skeletal muscle. However, mitochondrial dysfunction characterized by mitochondrial dynamic imbalance and mitophagy disruption can lead to varying degrees of muscle atrophy, but the underlying mechanism of action is still unclear. Although mitochondrial dynamics and mitophagy are two different mitochondrial quality control mechanisms, a large amount of evidence has indicated that they are interrelated and mutually regulated. The former maintains the balance of the mitochondrial network, eliminates damaged or aged mitochondria, and enables cells to survive normally. The latter degrades damaged or aged mitochondria through the lysosomal pathway, ensuring cellular functional health and metabolic homeostasis. Skeletal muscle atrophy is considered an urgent global health issue. Understanding and gaining knowledge about muscle atrophy caused by mitochondrial dysfunction, particularly focusing on mitochondrial dynamics and mitochondrial autophagy, can greatly contribute to the prevention and treatment of muscle atrophy. In this review, we critically summarize the recent research progress on mitochondrial dynamics and mitophagy in skeletal muscle atrophy, and expound on the intrinsic molecular mechanism of skeletal muscle atrophy caused by mitochondrial dynamics and mitophagy. Importantly, we emphasize the potential of targeting mitochondrial dynamics and mitophagy as therapeutic strategies for the prevention and treatment of muscle atrophy, including pharmacological treatment and exercise therapy, and summarize effective methods for the treatment of skeletal muscle atrophy.

Keywords:  Intermodulation; Mitochondrial dynamics; Mitophagy; Molecular mechanism; Prevention and treatment; Skeletal muscle atrophy

DOI:  https://doi.org/10.1186/s11658-024-00572-y
Mitochondrion. 2024 Apr 23. pii: S1567-7249(24)00044-8. [Epub ahead of print] 101886

Mitochondrial dysfunction, a weakest link of network of aging, relation to innate intramitochondrial immunity of DNA recognition receptors.

Dun-Xian Tan.

  Aging probably is the most complexed process in biology. It is manifested by a variety of hallmarks. These hallmarks weave a network of aging; however, each hallmark is not uniformly strong for the network. It is the weakest link determining the strengthening of the network of aging, or the maximum lifespan of an organism. Therefore, only improvement of the weakest link has the chance to increase the maximum lifespan but not others. We hypothesize that mitochondrial dysfunction is the weakest link of the network of aging. It may origin from the innate intramitochondrial immunity related to the activity of pathogen DNA recognition receptors. These receptors recognize mtDNA as the PAMP or DAMP to initiate the immune or inflammatory reactions. Evidence has shown that several of these receptors including TLR9, cGAS and IFI16 can be translocated into mitochondria. The potentially intramitochondrial pathogen DNA recognition receptors have the capacity to attack the exposed second structures of the mtDNA during its transcriptional or especially the replication processed, leading to the mtDNA mutation, deletion, heteroplasmy colonization, mitochondrial dysfunction, and alterations of other hallmarks, as well as aging. Pre-consumption of the intramitochondrial pathogen DNA recognition receptors by medical interventions including development of mitochondrial targeted small molecule which can neutralization of these receptors may retard or even reverse the aging to significantly improve the maximum lifespan of the organisms.

Keywords:  Aging; DNA recognition receptors; Hallmarks of aging; Innate intracellular immunity; Mitochondria dysfunction; mtDNA deletion

DOI:  https://doi.org/10.1016/j.mito.2024.101886
J Cardiovasc Transl Res. 2024 Apr 22.

Progress of Mitochondrial Function Regulation in Cardiac Regeneration.

Yi-Xi Chen, An-Ran Zhao, Tian-Wen Wei, Hao Wang, Lian-Sheng Wang.

  Heart failure and myocardial infarction, global health concerns, stem from limited cardiac regeneration post-injury. Myocardial infarction, typically caused by coronary artery blockage, leads to cardiac muscle cell damage, progressing to heart failure. Addressing the adult heart's minimal self-repair capability is crucial, highlighting cardiac regeneration research's importance. Studies reveal a metabolic shift from anaerobic glycolysis to oxidative phosphorylation in neonates as a key factor in impaired cardiac regeneration, with mitochondria being central. The heart's high energy demands rely on a robust mitochondrial network, essential for cellular energy, cardiac health, and regenerative capacity. Mitochondria's influence extends to redox balance regulation, signaling molecule interactions, and apoptosis. Changes in mitochondrial morphology and quantity also impact cardiac cell regeneration. This article reviews mitochondria's multifaceted role in cardiac regeneration, particularly in myocardial infarction and heart failure models. Understanding mitochondrial function in cardiac regeneration aims to enhance myocardial infarction and heart failure treatment methods and insights.

Keywords:  Cardiac Regeneration; Metabolism; Mitochondria; Oxidative Stress

DOI:  https://doi.org/10.1007/s12265-024-10514-w
J Nanobiotechnology. 2024 Apr 20. 22(1): 195

Exosomal miR-9-5p derived from iPSC-MSCs ameliorates doxorubicin-induced cardiomyopathy by inhibiting cardiomyocyte senescence.

Huifeng Zheng, Xiaoting Liang, Baojuan Liu, Xinran Huang, Ying Shen, Fang Lin, Jiaqi Chen, Xiaoyan Gao, Haiwei He, Weifeng Li, Bei Hu, Xin Li, Yuelin Zhang.

  Doxorubicin (DOX) is a chemotherapeutic agent widely used for tumor treatment. Nonetheless its clinical application is heavily limited by its cardiotoxicity. There is accumulated evidence that transplantation of mesenchymal stem cell-derived exosomes (MSC-EXOs) can protect against Dox-induced cardiomyopathy (DIC). This study aimed to examine the cardioprotective effects of EXOs isolated from human induced pluripotent stem cell-derived MSCs (iPSC-MSCs) against DIC and explore the potential mechanisms. EXOs were isolated from the cultural supernatant of human BM-MSCs (BM-MSC-EXOs) and iPSC-MSCs (iPSC-MSC-EXOs) by ultracentrifugation. A mouse model of DIC was induced by intraperitoneal injection of Dox followed by tail vein injection of PBS, BM-MSC-EXOs, or iPSC-MSC-EXOs. Cardiac function, cardiomyocyte senescence and mitochondrial dynamics in each group were assessed. In vitro, neonatal mouse cardiomyocytes (NMCMs) were subjected to Dox and treated with BM-MSC-EXOs or iPSC-MSC-EXOs. The mitochondrial morphology and cellular senescence of NMCMs were examined by Mitotracker staining and senescence-associated-β-galactosidase assay, respectively. Compared with BM-MSC-EXOs, mice treated with iPSC-MSC-EXOs displayed improved cardiac function and decreased cardiomyocyte mitochondrial fragmentation and senescence. In vitro, iPSC-MSC-EXOs were superior to BM-MSC-EXOs in attenuation of cardiomyocyte mitochondrial fragmentation and senescence caused by DOX. MicroRNA sequencing revealed a higher level of miR-9-5p in iPSC-MSC-EXOs than BM-MSC-EXOs. Mechanistically, iPSC-MSC-EXOs transported miR-9-5p into DOX-treated cardiomyocytes, thereby suppressing cardiomyocyte mitochondrial fragmentation and senescence via regulation of the VPO1/ERK signal pathway. These protective effects and cardioprotection against DIC were largely reversed by knockdown of miR-9-5p in iPSC-MSC-EXOs. Our results showed that miR-9-5p transferred by iPSC-MSC-EXOs protected against DIC by alleviating cardiomyocyte senescence via inhibition of the VPO1/ERK pathway. This study offers new insight into the application of iPSC-MSC-EXOs as a novel therapeutic strategy for DIC treatment.

Keywords:  Cardiomyopathy; Doxorubicin; Exosomes; Mesenchymal stem cells; Senescence

DOI:  https://doi.org/10.1186/s12951-024-02421-8