bims-mitrat Biomed News
on Mitochondrial Transplantation and Transfer
Issue of 2024–03–10
seven papers selected by
Gökhan Burçin Kubat, Gulhane Health Sciences Institute
  1. Exploring the limitations of mitochondrial dye as a genuine horizontal mitochondrial transfer surrogate.
  2. Mitotherapy inhibits against tenofovir induced nephrotoxicity on rat renal proximal tubular cells.
  3. Tunneling nanotubes: The transport highway for astrocyte-neuron communication in the central nervous system.
  4. Stem Leydig cells support macrophage immunological homeostasis through mitochondrial transfer in mice.
  5. Miro-mediated mitochondrial transport: A new dimension for disease-related abnormal cell metabolism?
  6. Therapeutic potential of mitochondrial transplantation in modulating immune responses post-cardiac arrest: a narrative review.
  7. Mito-metformin protects against mitochondrial dysfunction and dopaminergic neuronal degeneration by activating upstream PKD1 signaling in cell culture and MitoPark animal models of Parkinson's disease.
  1. Commun Biol. 2024 Mar 07. 7(1): 281
    Exploring the limitations of mitochondrial dye as a genuine horizontal mitochondrial transfer surrogate.
    Chuanfang Chen, Haige Li, Jia Zhang, Shih-Chin Cheng.
      Rosamine-based mitochondrial dyes, such as Mitotracker Red, have commonly been employed to visualize mitochondrial localization within cells due to their preferential accumulation in organelles with membrane potential. Consequently, Mitotracker Red has often served as a surrogate indicator for tracking mitochondrial movement between neighboring cells. However, it is important to note that the presence of membrane potential in the cell membrane and other organelles may lead to the non-specific partial enrichment of Mitotracker Red in locations other than mitochondria. This study comprehensively investigates the reliability of mitochondrial dye as a marker for studying horizontal mitochondrial transfer (HMT). By meticulous replicating of previous experiments and comparing the efficiency of mitochondrial dye transfer with that of mito-targeted GFP, our findings confirm that HMT occurs at significantly lower efficiency than previously indicated by Mitotracker dye. Subsequent experiments involving mitochondria-deficient cells robustly demonstrates the non-specificity of mitochondrial dye as indicator for mitochondria. We advocate for a thorough reevaluation of existing literature in this field and propose exploration of alternative techniques to enhance the investigation of HMT. By addressing these pivotal aspects, we can advance our understanding of cellular dynamics and pave the way for future explorations in this captivating field.
    DOI:  https://doi.org/10.1038/s42003-024-05964-6
  2. Biochem Biophys Rep. 2024 Jul;38 101669
    Mitotherapy inhibits against tenofovir induced nephrotoxicity on rat renal proximal tubular cells.
    Mir-Jamal Hosseini, Aysan Hassanbeigloo, Hamideh Abbasi, Abdollah Arjmand, Fatemeh Sherkat, Jalal Pourahmad.
      Tenofovir, as nucleotide reverse transcriptase inhibitors (NRTIs), is used to prevent and cure HIV/AIDS. Ample evidence confirmed that the nephrotoxicity of tenofovir has been linked to mitochondrial dysfunction. It seems that transplantation with healthy mitochondria instead of damaged mitochondria may be a beneficial approach to therapy. Therefore, it decided to investigate the impact of mitotherapy on tenofovir against renal proximal tubular cells (RPTCs) toxicity by measurement of oxidative stress and cytotoxicity biomarkers and restoring of mitochondrial function on isolated mitochondria. EC50 of tenofovir was achieved at 40 μM following 2 h incubation in Earle's solution (pH = 7.4; 37 °C). Freshly isolated mitochondria (80 μg/ml) were added to damage RPTCs affected by tenofovir in treated groups. One Way ANOVA analysis showed that healthy mitochondrial transplantation decreased oxidative stress biomarkers following tenofovir toxicity in RPTCs. Our data revealed that mitotherapy makes cell survival possible in RPTCs affected by tenofovir. In addition, it supposed that a novel and ideal strategy for the treatment of chemicals-induced nephrotoxicity.
    Keywords:  Mitochondrial transplantation; Nephrotoxicity; Oxidative stress; Renal proximal tubular cells (RPTCs); Tenofovir
    DOI:  https://doi.org/10.1016/j.bbrep.2024.101669
  3. Brain Res Bull. 2024 Mar 05. pii: S0361-9230(24)00054-6. [Epub ahead of print]209 110921
    Tunneling nanotubes: The transport highway for astrocyte-neuron communication in the central nervous system.
    Cuixiang Zhou, Min Huang, Shasha Wang, Shifeng Chu, Zhao Zhang, Naihong Chen.
      Tunneling nanotubes (TNTs) have emerged as pivotal structures for intercellular communication, enabling the transfer of cellular components across distant cells. Their involvement in neurological disorders has attracted considerable scientific interest. This review delineates the functions of TNTs within the central nervous system, examining their role in the transmission of bioenergetic substrates, and signaling molecules, and their multifaceted impact on both physiological and pathological processes, with an emphasis on neurodegenerative diseases. The review highlights the selectivity and specificity of TNTs as dedicated pathways for intercellular cargo delivery, particularly under stress conditions that provoke increased TNT formation. The potential of TNTs as therapeutic targets is explored in depth. We pay particular attention to the interactions between astrocytes and neurons mediated by TNTs, which are fundamental to brain architecture and function. Dysfunctions in these interactions are implicated in the spread of protein aggregates and mitochondrial anomalies, contributing to the pathogenesis of neurodegenerative diseases. The review culminates with a synthesis of the current understanding of TNT biology and identifies research gaps, advocating for intensified exploration into TNTs as a promising therapeutic frontier.
    Keywords:  Cellular stress; Intercellular communication; Neurodegenerative diseases; Pathogenic protein aggregates; Tunneling nanotubes
    DOI:  https://doi.org/10.1016/j.brainresbull.2024.110921
  4. Nat Commun. 2024 Mar 08. 15(1): 2120
    Stem Leydig cells support macrophage immunological homeostasis through mitochondrial transfer in mice.
    Ani Chi, Bicheng Yang, Hao Dai, Xinyu Li, Jiahui Mo, Yong Gao, Zhihong Chen, Xin Feng, Menghui Ma, Yanqing Li, Chao Yang, Jie Liu, Hanchao Liu, Zhenqing Wang, Feng Gao, Yan Liao, Xuetao Shi, Chunhua Deng, Min Zhang.
      As testicular mesenchymal stromal cells, stem Leydig cells (SLCs) show great promise in the treatment of male hypogonadism. The therapeutic functions of mesenchymal stromal cells are largely determined by their reciprocal regulation by immune responses. However, the immunoregulatory properties of SLCs remain unclear. Here, we observe that SLCs transplantation restore male fertility and testosterone production in an ischemia‒reperfusion injury mouse model. SLCs prevent inflammatory cascades through mitochondrial transfer to macrophages. Reactive oxygen species (ROS) released from activated macrophages inducing mitochondrial transfer from SLCs to macrophages in a transient receptor potential cation channel subfamily member 7 (TRPM7)-mediated manner. Notably, knockdown of TRPM7 in transplanted SLCs compromised therapeutic outcomes in both testicular ischemia‒reperfusion and testicular aging mouse models. These findings reveal a new mechanism of SLCs transplantation that may contribute to preserve testis function in male patients with hypogonadism related to immune disorders.
    DOI:  https://doi.org/10.1038/s41467-024-46190-2
  5. Biochem Biophys Res Commun. 2024 Feb 27. pii: S0006-291X(24)00273-0. [Epub ahead of print]705 149737
    Miro-mediated mitochondrial transport: A new dimension for disease-related abnormal cell metabolism?
    Yanxing Li, Zhen Yang, Shumei Zhang, Jianjun Li.
      Mitochondria are versatile and highly dynamic organelles found in eukaryotic cells that play important roles in a variety of cellular processes. The importance of mitochondrial transport in cell metabolism, including variations in mitochondrial distribution within cells and intercellular transfer, has grown in recent years. Several studies have demonstrated that abnormal mitochondrial transport represents an early pathogenic alteration in a variety of illnesses, emphasizing its significance in disease development and progression. Mitochondrial Rho GTPase (Miro) is a protein found on the outer mitochondrial membrane that is required for cytoskeleton-dependent mitochondrial transport, mitochondrial dynamics (fusion and fission), and mitochondrial Ca2+ homeostasis. Miro, as a critical regulator of mitochondrial transport, has yet to be thoroughly investigated in illness. This review focuses on recent developments in recognizing Miro as a crucial molecule in controlling mitochondrial transport and investigates its roles in diverse illnesses. It also intends to shed light on the possibilities of targeting Miro as a therapeutic method for a variety of diseases.
    Keywords:  Cancer; Cell metabolism; Central nervous system disease; Miro; Mitochondrial transport; Tunneling nanotuble
    DOI:  https://doi.org/10.1016/j.bbrc.2024.149737
  6. J Transl Med. 2024 Mar 03. 22(1): 230
    Therapeutic potential of mitochondrial transplantation in modulating immune responses post-cardiac arrest: a narrative review.
    Tomoaki Aoki, Yusuke Endo, Eriko Nakamura, Cyrus E Kuschner, Jacob Kazmi, Parmeshar Singh, Tai Yin, Lance B Becker, Kei Hayashida.
       BACKGROUND: Mitochondrial transplantation (MTx) has emerged as a novel therapeutic strategy, particularly effective in diseases characterized by mitochondrial dysfunction. This review synthesizes current knowledge on MTx, focusing on its role in modulating immune responses and explores its potential in treating post-cardiac arrest syndrome (PCAS).
    METHODS: We conducted a comprehensive narrative review of animal and human studies that have investigated the effects of MTx in the context of immunomodulation. This included a review of the immune responses following critical condition such as ischemia reperfusion injury, the impact of MTx on these responses, and the therapeutic potential of MTx in various conditions.
    RESULTS: Recent studies indicate that MTx can modulate complex immune responses and reduce ischemia-reperfusion injury post-CA, suggesting MTx as a novel, potentially more effective approach. The review highlights the role of MTx in immune modulation, its potential synergistic effects with existing treatments such as therapeutic hypothermia, and the need for further research to optimize its application in PCAS. The safety and efficacy of autologous versus allogeneic MTx, particularly in the context of immune reactions, are critical areas for future investigation.
    CONCLUSION: MTx represents a promising frontier in the treatment of PCAS, offering a novel approach to modulate immune responses and restore cellular energetics. Future research should focus on long-term effects, combination therapies, and personalized medicine approaches to fully harness the potential of MTx in improving patient outcomes in PCAS.
    Keywords:  Cardiopulmonary resuscitation; Heart arrest; Immune response; Inflammation; Ischemia; Mitochondrial transplantation; Reperfusion injury
    DOI:  https://doi.org/10.1186/s12967-024-05003-2
  7. Front Neurosci. 2024 ;18 1356703
    Mito-metformin protects against mitochondrial dysfunction and dopaminergic neuronal degeneration by activating upstream PKD1 signaling in cell culture and MitoPark animal models of Parkinson's disease.
    Muhammet Ay, Adhithiya Charli, Monica Langley, Ahyoung Jang, Piyush Padhi, Huajun Jin, Vellareddy Anantharam, Balaraman Kalyanaraman, Arthi Kanthasamy, Anumantha G Kanthasamy.
      Impaired mitochondrial function and biogenesis have strongly been implicated in the pathogenesis of Parkinson's disease (PD). Thus, identifying the key signaling mechanisms regulating mitochondrial biogenesis is crucial to developing new treatment strategies for PD. We previously reported that protein kinase D1 (PKD1) activation protects against neuronal cell death in PD models by regulating mitochondrial biogenesis. To further harness the translational drug discovery potential of targeting PKD1-mediated neuroprotective signaling, we synthesized mito-metformin (Mito-Met), a mitochondria-targeted analog derived from conjugating the anti-diabetic drug metformin with a triphenylphosphonium functional group, and then evaluated the preclinical efficacy of Mito-Met in cell culture and MitoPark animal models of PD. Mito-Met (100-300 nM) significantly activated PKD1 phosphorylation, as well as downstream Akt and AMPKα phosphorylation, more potently than metformin, in N27 dopaminergic neuronal cells. Furthermore, treatment with Mito-Met upregulated the mRNA and protein expression of mitochondrial transcription factor A (TFAM) implying that Mito-Met can promote mitochondrial biogenesis. Interestingly, Mito-Met significantly increased mitochondrial bioenergetics capacity in N27 dopaminergic cells. Mito-Met also reduced mitochondrial fragmentation induced by the Parkinsonian neurotoxicant MPP+ in N27 cells and protected against MPP+-induced TH-positive neurite loss in primary neurons. More importantly, Mito-Met treatment (10 mg/kg, oral gavage for 8 week) significantly improved motor deficits and reduced striatal dopamine depletion in MitoPark mice. Taken together, our results demonstrate that Mito-Met possesses profound neuroprotective effects in both in vitro and in vivo models of PD, suggesting that pharmacological activation of PKD1 signaling could be a novel neuroprotective translational strategy in PD and other related neurocognitive diseases.
    Keywords:  MitoPark; PKD1; Parkinson’s disease; metformin; mitochondria; mitochondrial biogenesis; neuroprotection
    DOI:  https://doi.org/10.3389/fnins.2024.1356703
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